Pyrazolopyridine-1,4-Diamines and Analogs Thereof

ABSTRACT

Pyrazolopyridine-1,4-diamines and analogs thereof, e.g., pyrazolo[3,4-c]pyridine-1,4-diamines, pyrazolo[3,4-c]quinoline-1,4-diamines, 6,7,8,9-tetrahydro pyrazolo[3,4-c]quinoline-1,4-diamines, and pyrazolo[3,4-c]naphthyridine-1,4-di-amines, pharmaceutical compositions containing the compounds, intermediates, methods of making these compounds, and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

The present invention claims priority to U.S. Provisional ApplicationSer. No. 60/667,828, filed Apr. 1, 2005, which is incorporated herein byreference.

BACKGROUND

Certain compounds have been found to be useful as immune responsemodifiers (IRMs), rendering them useful in the treatment of a variety ofdisorders. However, there continues to be interest in and a need forcompounds that have the ability to modulate the immune response, byinduction of cytokine biosynthesis or other means.

SUMMARY

The present invention provides a new class of compounds that are usefulin inducing cytokine biosynthesis in animals. Such compounds are of thefollowing Formula I:

wherein R_(A), R_(B), R₁, R₁′, and R″ are as defined below.

The compounds of Formula I are useful as immune response modifiers dueto their ability to induce cytokine biosynthesis (e.g., induces thesynthesis of at least one cytokine) and otherwise modulate the immuneresponse when administered to animals. This makes the compounds usefulin the treatment of a variety of conditions such as viral diseases andtumors that are responsive to such changes in the immune response.

The invention further provides pharmaceutical compositions containing aneffective amount of a compound of Formula I and methods of inducingcytokine biosynthesis in an animal, treating a viral infection ordisease and/or treating a neoplastic disease in an animal byadministering an effective amount of a compound of Formula I to theanimal.

In addition, methods of synthesizing compounds of Formula I andintermediates useful in the synthesis of these compounds are provided.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably.

The terms “comprises” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the description,guidance is provided through lists of examples, which examples can beused in various combinations. In each instance, the recited list servesonly as a representative group and should not be interpreted as anexclusive list.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

The present invention provides compounds of the following Formula I:

and more specifically compounds of the following Formulas II, III, IV,V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, and XVI:

wherein R_(A), R_(B), R_(A1), R_(B1), R_(A2), R_(B2), R, R₁, R₁′, R″,R₂, R₃, X₁, A₁, G, m, n, and p are as defined below; andpharmaceutically acceptable salts thereof.

In one embodiment, the present invention provides a compound of theFormula I: wherein:

R₁ is selected from the group consisting of:

-   -   —R₄,    -   —Y—R₄,    -   —X—N(R₈)—Y—R₄,    -   —X—C(R₆)—N(R₈)—R₄,    -   —X—O—C(R₆)—N(R₉)—R₄,    -   —X—S(O—N(R₈)—R₄,    -   —X—O—R₄, and    -   —X—R₅;

R₁′ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl groupcontains at least two carbon atoms between the hydroxy or alkoxysubstituent and the nitrogen atom to which R₁′ is bonded;

or R₁ and R₁′ together with the nitrogen atom to which they are bondedcan join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—;

X is C₂₋₂₀ alkylene;

Y is selected from the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—,—S(O)₂—N(R₈)—, and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from thegroup consisting of hydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄together with the nitrogen atom to which R₁₁ is bonded can join to formthe group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R)— then a and b areindependently integers from 2 to 4;

R_(A) and R_(B) are each independently selected from the groupconsisting of:

-   -   hydrogen,    -   halogen,    -   alkyl,    -   alkenyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

or when taken together, R_(A) and R_(B) form a fused aryl ring orheteroaryl ring containing one heteroatom selected from the groupconsisting of N and S, wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R′ groups;

or when taken together, R_(A) and R_(B) form a fused 5 to 7 memberedsaturated ring, optionally containing one heteroatom selected from thegroup consisting of N and S, and unsubstituted or substituted by one ormore R groups;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstitutedor substituted by one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,dialkylamino, and in the case of alkyl, alkenyl, alkynyl, andheterocyclyl, oxo, with the proviso that when R₁ is R₄, and R₄ is asubstituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁ is bonded;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R′ is a non-interfering substituent; and

R″ is hydrogen or a non-interfering substituent;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of theFormula II:

wherein:

R₁ is selected from the group consisting of:

-   -   —R₄,    -   —Y—R₄,    -   —X—N(R₈)—Y—R₄,    -   —X—C(R₆)—N(R₈)—R₄,    -   —X—O—C(R₆)—N(N₈)—R₄,    -   —X—S(O)₂—N(R₈)—R₄,    -   —X—O—R₄, and    -   —X—R₅;

R₁′ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl groupcontains at least two carbon atoms between the hydroxy or alkoxysubstituent and the nitrogen atom to which R₁′ is bonded;

or R₁ and R₁′ together with the nitrogen atom to which they are bondedcan join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—;

X is C₂₋₂₀ alkylene;

Y is selected from the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—,—S(O)₂—N(R₈)—, and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from thegroup consisting of hydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄together with the nitrogen atom to which R₁₁ is bonded can join to formthe group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4;

R_(A1) and R_(B1) are each independently selected from the groupconsisting of:

-   -   hydrogen,    -   halogen,    -   alkyl,    -   alkenyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

or when taken together, R_(A1) and R_(B1) form a fused aryl ring orheteroaryl ring containing one heteroatom selected from the groupconsisting of N and S, wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R groups, or substituted byone R₃ group, or substituted by one R₃ group and one R group;

or when taken together, R_(A1) and R_(B1) form a fused 5 to 7 memberedsaturated ring, optionally containing one heteroatom selected from thegroup consisting of N and S, and unsubstituted or substituted by one ormore R groups;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

R₂ is selected from the group consisting of:

-   -   —R₄′,    -   —X′—R₄′,    -   —X′—Y′—R₄′, and    -   —X′—R₅′;

R₃ is selected from the group consisting of:

-   -   -Z-R₄′,    -   -Z-x′—R₄′,    -   -Z-x′—Y′—R₄′,    -   -Z-x′—Y′—X′—Y′—R₄′, and    -   -Z-x′—R₅′;

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstitutedor substituted by one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,dialkylamino, and in the case of alkyl, alkenyl, alkynyl, andheterocyclyl, oxo, with the proviso that when R₁ is R₄, and R₄ is asubstituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁ is bonded;

R₄′ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A′ is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

A″ is selected from the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—,and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—,—C(R₆)—S—, and —C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;

X′ is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated by arylene, heteroarylene or heterocyclyleneand optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

Z is a bond or —O—; and

c and d are independently integers from 1 to 6 with the proviso that c+dis ≦7; or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of theFormula III:

wherein:

R₁ is selected from the group consisting of:

-   -   —R₄,    -   —Y—R₄,    -   —X—N(R₈)—Y—R₄,    -   —X—C(R₆)—N(R₈)—R₄,    -   —X—O—C(R₆)—N(R₈)—R₄,    -   —X—S(O)₂—N(R₈)—R₄,    -   —X—O—R₄, and    -   —X—R₅;

R₁′ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl groupcontains at least two carbon atoms between the hydroxy or alkoxysubstituent and the nitrogen atom to which R₁′ is bonded;

or R₁ and R₁′ together with the nitrogen atom to which they are bondedcan join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—;

X is C₂₋₂₀ alkylene;

Y is selected from the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—,—S(O)₂—N(R₈)—, and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from thegroup consisting of hydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄together with the nitrogen atom to which R₁₁ is bonded can join to formthe group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4;

R_(A2) and R_(B2) are each independently selected from the groupconsisting of:

-   -   hydrogen,    -   halogen,    -   alkyl,    -   alkenyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

R₂ is selected from the group consisting of:

-   -   —R₄′,    -   —X′—R₄′,    -   —X′—Y′—R₄′, and    -   —X′—R₅′;

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl,alkyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,dialkylamino, and in the case of alkyl, alkenyl, alkynyl, andheterocyclyl, oxo, with the proviso that when R₁ is R₄, and R₄ is asubstituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁ is bonded;

R₄′ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A′ is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

A″ is selected from the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—,and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—,—C(R₆)—S—, and —C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₉)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;

X′ is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated by arylene, heteroarylene or heterocyclyleneand optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

c and d are independently integers from 1 to 6 with the proviso that c+dis ≦7; or a pharmaceutically acceptable salt thereof

In another embodiment, the present invention provides a compound of theFormula IV:

wherein:

R₁ is selected from the group consisting of:

-   -   —R₄,    -   —Y—R₄,    -   —X—N(R₈)—Y—R₄,    -   —X—C(R₆)—N(R₈)—R₄,    -   —X—O—C(R₆)—N(R₈)—R₄,    -   —X—S(O)₂—N(R₈)—R₄,    -   —X—O—R₄, and    -   —X—R₅;

R₁′ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl groupcontains at least two carbon atoms between the hydroxy or alkoxysubstituent and the nitrogen atom to which R₁′ is bonded;

or R₁ and R₁′ together with the nitrogen atom to which they are bondedcan join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—;

X is C₂₋₂₀ alkylene;

Y is selected from the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—,—S(O)₂—N(R₈)—, and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from thegroup consisting of hydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄together with the nitrogen atom to which R₁₁ is bonded can join to formthe group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

n is an integer from 0 to 4;

R₂ is selected from the group consisting of:

-   -   —R₄′,    -   —X′—R₄′,    -   —X′—Y′—R₄′, and    -   —X′—R₅′;

R₃ is selected from the group consisting of:

-   -   -Z-R₄′,    -   -Z-x′—R₄′,    -   -Z-x′—Y′—R₄′,    -   -Z-x′—Y′—X′—Y′—R₄′, and    -   -Z-x′—R₅′;

m is 0 or 1 with the proviso that when m is 1 then n is 0 or 1;

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstitutedor substituted by one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,dialkylamino, and in the case of alkyl, alkenyl, alkynyl, andheterocyclyl, oxo, with the proviso that when R₁ is R₄, and R₄ is asubstituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁ is bonded;

R₄′ is selected from the group consisting of hydrogen, allyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A′ is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

A″ is selected from the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—,and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—,—C(R₆)—S—, and —C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;

X′ is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated by arylene, heteroarylene or heterocyclyleneand optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

Z is a bond or —O—; and

c and d are independently integers from 1 to 6 with the proviso that c+dis ≦7; or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of theFormula V:

wherein:

R₁ is selected from the group consisting of:

-   -   —R₄,    -   —X—N(R₈)—Y—R₄,    -   —X—C(R₆)—N(R₈)—R₄,    -   —X—O—C(R₆)—N(R₈)—R₄,    -   —X—S(O)₂—N(R₈)—R₄,    -   —X—O—R₄, and    -   —X—R₅;

R₁′ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl groupcontains at least two carbon atoms between the hydroxy or alkoxysubstituent and the nitrogen atom to which R₁′ is bonded;

or R₁ and R₁′ together with the nitrogen atom to which they are bondedcan join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—;

X is C₂₋₂₀ alkylene;

Y is selected from the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—,—S(O)₂—N(R₈)—, and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from thegroup consisting of hydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄together with the nitrogen atom to which R₁₁ is bonded can join to formthe group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

n is an integer from 0 to 4;

R₂ is selected from the group consisting of:

-   -   R₄′,    -   —X′—R₄′,    -   —X′—Y′—R₄′, and    -   —X′—R₅′;

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstitutedor substituted by one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,dialkylamino, and in the case of alkyl, alkenyl, alkynyl, andheterocyclyl, oxo, with the proviso that when R₁ is R₄, and R₄ is asubstituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁ is bonded;

R₄′ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A′ is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

A″ is selected from the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—,and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—,—C(R₆)—S—, and —C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)—;

X′ is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated by arylene, heteroarylene or heterocyclyleneand optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

and

c and d are independently integers from 1 to 6 with the proviso that c+dis ≦7; or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compoundselected from the group consisting of the Formulas VI, VII, VIII, andIX:

wherein:

R₁ is selected from the group consisting of:

-   -   —R₄,    -   —Y—R₄,    -   —X—N(R₈)—Y—R₄,    -   —X—C(R₆)—N(R₈)—R₄,    -   —X—O—C(R₆)—N(R₈)—R₄,    -   —X—S(O)₂—N(R₈)—R₄,    -   —X—O—R₄, and    -   —X—R₅;

R₁′ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl groupcontains at least two carbon atoms between the hydroxy or alkoxysubstituent and the nitrogen atom to which R₁′ is bonded;

or R₁ and R₁′ together with the nitrogen atom to which they are bondedcan join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—;

X is C₂₋₂₀ alkylene;

Y is selected from the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—,—S(O)₂—N(R₈)—, and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from thegroup consisting of hydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄together with the nitrogen atom to which R₁₁ is bonded can join to formthe group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

p is an integer from 0 to 3;

R₂ is selected from the group consisting of:

-   -   —R₄′,    -   —X′—R₄′,    -   —X′—Y′—R₄, and    -   —X′—R₄′;

R₃ is selected from the group consisting of:

-   -   -Z-x′—R₄′,    -   -Z-x′—Y′—R₄′,    -   -Z-x′—Y′—X′—Y′—R₄′, and    -   -Z-x′—R₅′;

m is 0 or 1 with the proviso that when m is 1 then p is 0 or 1;

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstitutedor substituted by one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,dialkylamino, and in the case of alkyl, alkenyl, alkynyl, andheterocyclyl, oxo, with the proviso that when R₁ is R₄, and R₄ is asubstituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁ is bonded;

R₄′ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A′ is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—;

A″ is selected from the group consisting of —O—, —S(O)_(0.2)—,—N(-Q-R₄)—, and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₉)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—,—C(R₆)—S—, and —C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;

X′ is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated by arylene, heteroarylene or heterocyclyleneand optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

Z is a bond or —O—; and

c and d are independently integers from 1 to 6 with the proviso that c+dis ≦7; or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compoundselected from the group consisting of the Formulas X, XI, XII, and XIII:

wherein:

R₁ is selected from the group consisting of:

-   -   —R₄,    -   Y—R₄,    -   —X—N(R₈)—Y—R₄,    -   —X—C(R₆)—N(R₈)—R₄,    -   —X—O—C(R₆)—N(R₈)—R₄,    -   —X—S(O)₂—N(R₈)—R₄,    -   —X—O—R₄, and    -   —X—R₅;

R₁′ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl groupcontains at least two carbon atoms between the hydroxy or alkoxysubstituent and the nitrogen atom to which R₁′ is bonded;

or R₁ and R₁′ together with the nitrogen atom to which they are bondedcan join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—;

X is C₂₋₂₀ alkylene;

Y is selected from the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—,—S(O)₂—N(R₈)—, and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from thegroup consisting of hydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄together with the nitrogen atom to which R₁₁ is bonded can join to formthe group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₉)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

p is an integer from 0 to 3;

R₂ is selected from the group consisting of:

-   -   —R₄′,    -   —X′—R₄′,    -   —X′—Y′—R₄′, and    -   —X′—R₅′;

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstitutedor substituted by one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,dialkylamino, and in the case of alkyl, alkenyl, alkynyl, andheterocyclyl, oxo, with the proviso that when R₁ is R₄, and R₄ is asubstituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁ is bonded;

R₄′ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A′ is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—, and—N(R₄)—; A″ is selected from the group consisting of —O—, —S(O)₀₋₂—,—N(-Q-R₄)—, and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—,—C(R₆)—S—, and —C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;

X′ is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated by arylene, heteroarylene or heterocyclyleneand optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

c and d are independently integers from 1 to 6 with the proviso that c+dis ≦7; or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of theFormula XIV:

wherein:

X₁ is a bond or C₁₋₄ alkylene;

A₁ is selected from the group consisting of —N(R₈)— and —N(—Y—R₄)—;

Y is selected from the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—,—S(O)₂—N(R₈)—, and —C(R₆)—N(R₁₁; wherein R₁₁ is selected from the groupconsisting of hydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄ togetherwith the nitrogen atom to which R₁₁ is bonded can join to form the group

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—;

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4;

X is C₂₋₂₀ alkylene; and

R₁′, R₂, R₄, R₆, R₈, R_(A1) and R_(B1) are defined as in Formula IIabove;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of theFormula XV:

wherein:

G is selected from the group consisting of:

-   -   —C(O)—R′″,    -   α-aminoacyl,    -   α-aminoacyl-α-aminoacyl,    -   —C(O)—O—R′″,    -   —C(O)—N(R″″)R′″,    -   —C(═NY₂)—R′″,    -   —CH(OH)—C(O)—OY₂,    -   —CH(OC₁₋₄ alkyl)Y₀,    -   —CH₂Y₁, and    -   —CH(CH₃)Y₁;

R′″ and R″″ are independently selected from the group consisting ofC₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, phenyl, benzyl, and 2-phenylethyl, each ofwhich may be unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of halogen, hydroxy,nitro, cyano, carboxy, C₁₋₆ alkyl, C₁₋₄ alkoxy, aryl, heteroaryl,aryl-C₁₋₄ alkylenyl, heteroaryl-C₁₋₄ alkylenyl, halo-C₁₋₄ alkylenyl,halo-C₁₋₄ alkoxy, —O—C(O)—CH₃, —C(O)—O—CH₃, —C(O)—NH₂, —O—CH₂—C(O)—NH₂,—NH₂, and —S(O)₂—NH₂, with the proviso that R″″ can also be hydrogen;

α-aminoacyl is an α-aminoacyl group derived from an α-amino acidselected from the group consisting of racemic, D-, and L-amino acids;

Y₂ is selected from the group consisting of hydrogen, C₁₋₆ alkyl, andbenzyl;

Y₀ is selected from the group consisting of C₁₋₆ alkyl, carboxy-C₁₋₆alkylenyl, amino-C₁₋₄ alkylenyl, mono-N—C₁₋₆ alkylamino-C₁₋₄ alkylenyl,and di-N,N—C₁₋₆ alkylamino-C₁₋₄ alkylenyl;

Y₁ is selected from the group consisting of mono-N—C₁₋₆ alkylamino,di-N,N—C₁₋₆ alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl,and 4-C₁₋₄ alkylpiperazin-1-yl; and

R₁, R₁′, R₂, R_(A1), and R_(B1), are defined as in Formula II above; ora pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of theFormula XVI:

wherein:

G is defined as in Formula XV above; and

X₁, A₁, R₁′, R₂, R_(A1), and R_(B1), are defined as in Formula XIVabove; or a pharmaceutically acceptable salt thereof.

Herein, “non-interfering” means that the ability of the compound orsalt, which contains a non-interfering substituent, to modulate (e.g.,induce) the biosynthesis of one or more cytokines is not destroyed bythe non-interfering substitutent. Illustrative non-interfering R′ groupsinclude those described herein for R and R₃. Illustrativenon-interfering R″ groups include those described herein for R₂.

As used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the prefix“alk-” are inclusive of both straight chain and branched chain groupsand of cyclic groups, e.g., cycloalkyl and cycloalkenyl. Unlessotherwise specified, these groups contain from 1 to 20 carbon atoms,with alkenyl groups containing from 2 to 20 carbon atoms, and alkynylgroups containing from 2 to 20 carbon atoms. In some embodiments, thesegroups have a total of up to 10 carbon atoms, up to 8 carbon atoms, upto 6 carbon atoms, or up to 4 carbon atoms. Cyclic groups can bemonocyclic or polycyclic and preferably have from 3 to 10 ring carbonatoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl,cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstitutedbornyl, norbornyl, and norbornenyl.

Unless otherwise specified, “alkylene”, “alkenylene”, and “alkynylene”are the divalent forms of the “alkyl”, “alkenyl”, and “alkynyl” groupsdefined above. The terms, “alkylenyl”, “alkenylenyl”, and “alkynylenyl”are used when “alkylene”, “alkenylene”, and “alkynylene”, respectively,are substituted. For example, an arylalkylenyl group comprises analkylene moiety to which an aryl group is attached.

The term “haloalkyl” is inclusive of groups that are substituted by oneor more halogen atoms, including perfluorinated groups. This is alsotrue of other groups that include the prefix “halo-”. Examples ofsuitable haloalkyl groups are chloromethyl, trifluoromethyl, and thelike.

The term “aryl” as used herein includes carbocyclic aromatic rings orring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl.

Unless otherwise indicated, the term “heteroatom” refers to the atoms O,S, or N.

The term “heteroaryl” includes aromatic rings or ring systems thatcontain at least one ring heteroatom (e.g., O, S, N). In someembodiments, the term “heteroaryl” includes a ring or ring system thatcontains 2-12 carbon atoms, 1-3 rings, 14 heteroatoms, and O, S, and Nas the heteroatoms. Suitable heteroaryl groups include furyl, thienyl,pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl,pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl,benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl,benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl,isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl,1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl,thiadiazolyl, and so on.

The term “heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring heteroatom (e.g., O, S, N) and includes all ofthe fully saturated and partially unsaturated derivatives of the abovementioned heteroaryl groups. In some embodiments, the term“heterocyclyl” includes a ring or ring system that contains 2-12 carbonatoms, 1-3 rings, 1-4 heteroatoms, and O, S, and N as the heteroatoms.Exemplary heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl,morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl,piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl,tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl),1,4-oxazepanyl, homopiperazinyl (diazepanyl), 1,3-dioxolanyl,aziridinyl, azetidinyl, dihydroisoquinolin-(1H)-yl,octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl,octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl,3-azabicyclo[3.2.2]non-3-yl, and the like.

The term “heterocyclyl” includes bicyclic and tricyclic heterocyclicring systems. Such ring systems include fused and/or bridged rings andspiro rings. Fused rings can include, in addition to a saturated orpartially saturated ring, an aromatic ring, for example, a benzene ring.Spiro rings include two rings joined by one spiro atom and three ringsjoined by two Spiro atoms.

The terms “arylene”, “heteroarylene”, and “heterocyclylene” are thedivalent forms of the “aryl”, “heteroaryl”, and “heterocyclyl” groupsdefined above. The terms, “arylenyl”, “heteroarylenyl”, and“heterocyclylenyl” are used when “arylene”, “heteroarylene”, and“heterocyclylene”, respectively, are substituted. For example, analkylarylenyl group comprises an arylene moiety to which an alkyl groupis attached.

The term “fused aryl ring” includes fused carbocyclic aromatic rings orring systems. Examples of fused aryl rings include benzo, naphtho,fluoreno, and indeno.

The term “fused heteroaryl ring” includes the fused forms of 5 or 6membered aromatic rings that contain one heteroatom selected from S andN.

The term “fused 5 to 7 membered saturated ring” includes rings which arefully saturated except for the bond where the ring is fused.

When a group (or substituent or variable) is present more than once inany formula described herein, each group (or substituent or variable) isindependently selected, whether explicitly stated or not. For example,for the formula —N(R₉)₂ each R₉ group is independently selected. Inanother example, when an R₂ and an R₃ group are both present and eachcontains a Y′ group, and each Y′ group contains an R₈ group, each Y′group is independently selected, and each R₈ group is independentlyselected.

The invention is inclusive of the compounds described herein and saltsthereof, in any of their pharmaceutically acceptable forms, includingisomers (e.g., diastereomers and enantiomers), solvates, polymorphs,prodrugs, and the like. In particular, if a compound is opticallyactive, the invention specifically includes each of the compound'senantiomers as well as racemic mixtures of the enantiomers. It should beunderstood that the term “compound” or the term “compounds” includes anyor all of such forms, whether explicitly stated or not (although attimes, “salts” are explicitly stated).

The term “prodrug” means a compound that can be transformed in vivo toyield an immune response modifying compound, including any of the salt,solvated, polymorphic, or isomeric forms described above. The prodrug,itself, may be an immune response modifying compound, including any ofthe salt, solvated, polymorphic, or isomeric forms described above. Thetransformation may occur by various mechanisms, such as through achemical (e.g., solvolysis or hydrolysis, for example, in the blood) orenzymatic biotransformation. A discussion of the use of prodrugs isprovided by T. Higuchi and W. Stella, “Pro-drugs as Novel DeliverySystems,” Vol. 14 of the A. C. S. Symposium Series, and in BioreversibleCarriers in Drug Design, ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987.

For example, if a compound of the present invention contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as C₁₋₈ alkyl, C₂₋₁₂ alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—C₁₋₂alkylaminoC₂₋₃ alkyl (such as β-dimethylaminoethyl), carbamoyl-C₁₋₂alkyl, N,N-diC₁₋₂ alkylcarbamoyl-C₁₋₂ alkyl and piperidino-,pyrrolidino-, or morpholinoC₂₋₃ alkyl.

If a compound of the present invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as C₁₋₆ alkanoyloxymethyl,1-(C₁₋₆ alkanoyloxy)ethyl, 1-methyl-1-(C₁₋₆ alkanoyloxy)ethyl, C₁₋₆alkoxycarbonyloxymethyl, N—(C₁₋₆ alkoxycarbonyl)aminomethyl, succinoyl,C₁ alkanoyl, α-aminoC₁₋₄ alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,P(O)(O—C₁₋₆ alkyl)₂ or glycosyl (the radical resulting from the removalof a hydroxyl group of the hemiacetal form of a carbohydrate).

A prodrug of a compound of the present invention can also be formed bythe replacement of a hydrogen atom in the amino group at the 4-position(and/or in an amino group at another position) with a group such asR′″-carbonyl, R′″-O-carbonyl, N(R″″)(R′″)-carbonyl, —C(—NY₂)—R′″, whereR′″ and R″″ are each independently C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, phenyl,benzyl, or 2-phenylethyl, α-aminoacyl, α-aminoacyl-α-aminoacyl,—C(OH)C(O)OY₂ wherein Y₂ is H, C₁₋₆ alkyl or benzyl, —C(OY₄)Y₀ whereinY₄ is C₁₋₄ alkyl and Y₀ is C₁₋₆ alkyl, carboxyC₁₋₆ alkyl, aminoC₁₋₄alkyl or mono-N— or di-N,N—C₁₋₆alkylaminoC₁₋₄ alkyl, —C(Y₅)Y₁ wherein Y₅is H or methyl and Y₁ is mon-N— or di-N,N—C₁₋₆ alkylamino, morpholino,piperidin-1-yl, pyrrolidin-1-yl, or 4-C₁₋₄ alkylpiperazin-1-yl.

For certain embodiments, a hydrogen atom in the amino group at the4-position (and/or in an amino group at another position) can bereplaced with a group such as R_(a)′″-carbonyl, R_(a)′″—O-carbonyl,N(R_(a)′″)(R_(a)′″)-carbonyl where R_(a)′″ and R_(a)″″ are eachindependently C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, benzyl, or R_(a)′″-carbonylis a natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl,—C(OH)C(O)OY₂ wherein Y₂ is H, C₁₋₆ alkyl or benzyl, —C(OY₄)Y_(0a)wherein Y₄ is C₁₋₄ alkyl and Y_(0a) is C₁₋₆ alkyl, carboxyC₁₋₆ alkyl,aminoC₁₋₄alkyl or mono-N— or di-N,N—C₁₋₆ alkylaminoalkyl, —C(Y₅)Y_(1a)wherein Y₅ is H or methyl and Y_(1a) is mon-N— or di-N,N—C₁₋₆alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

Compounds (including intermediates) of the present invention may existin different tautomeric forms, and all such forms are embraced withinthe scope of the invention. The term “tautomer” or “tautomeric form”refers to structural isomers of different energies which areinterconvertible via a low energy barrier. For example proton tautomers(prototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Whencompounds of the present invention have a hydrogen atom at the2-position, proton migration between the 2- and 3-positions may occur.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The present invention embraces bothsolvated and unsolvated forms.

For any of the compounds presented herein, each one of the followingvariables (e.g., R_(A), R_(B), R_(A1), R_(B1), R, R₁, R₂, m, n, p, G, Q,X, Y, Z, and so on) in any of its embodiments can be combined with anyone or more of the other variables in any of their embodiments andassociated with any one of the formulas described herein, as would beunderstood by one of skill in the art. Each of the resultingcombinations of variables is an embodiment of the present invention.

In certain embodiments (e.g., of Formula I), R_(A) and R_(B) are eachindependently selected from the group consisting of hydrogen, halogen,alkyl, alkenyl, alkoxy, alkylthio, and —N(R₉)₂;

or when taken together, R_(A) and R_(B) form a fused aryl ring orheteroaryl ring containing one heteroatom selected from the groupconsisting of N and S wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R′ groups;

or when taken together, R_(A) and R_(B) form a fused 5 to 7 memberedsaturated ring, optionally containing one heteroatom selected from thegroup consisting of N and S, and unsubstituted or substituted by one ormore R groups.

In certain embodiments (e.g., of Formula II, XIV, XV, or XVI), R_(A1)and R_(B1) are each independently selected from the group consisting ofhydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and —N(R₉)₂;

or when taken together, R_(A1) and R_(B1) form a fused aryl ring orheteroaryl ring containing one heteroatom selected from the groupconsisting of N and S, wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R groups, or substituted byone R₃ group, or substituted by one R₃ group and one R group;

or when taken together, R_(A1) and R_(B1) form a fused 5 to 7 memberedsaturated ring, optionally containing one heteroatom selected from thegroup consisting of N and S, and unsubstituted or substituted by one ormore R groups.

In certain embodiments (e.g., of Formula I or Formula II, XIV, XV, orXVI), R_(A) and R_(B) or R_(A1) and R_(B1) are each independentlyselected from the group consisting of hydrogen, halogen, alkyl, alkenyl,alkoxy, alkylthio, and —N(R₉)₂.

In certain embodiments (e.g., of Formula I or Formula II, XIV, XV, orXVI), R_(A) and R_(B) or R_(A1) and R_(B1) form a fused aryl orheteroaryl ring.

In certain embodiments (e.g., of Formula I), R_(A) and R_(B) are takentogether to form a fused aryl ring wherein the ring is a benzo ringwhich is unsubstituted or substituted by one, two, three, or four R′groups.

In certain embodiments (e.g., of Formula I or Formula II, XIV, XV, orXVI), R_(A) and R_(B) or R_(A1) and R_(B1) form a fused aryl ring. Incertain embodiments, the fused aryl ring is benzo.

In certain embodiments (e.g., of Formula II, XIV, XV, or XVI), R_(A1)and R_(B1) are taken together to form a fused aryl ring, wherein thering is a benzo ring which is unsubstituted or substituted by one ormore R groups, or substituted by one R₃ group, or substituted by one R₃group and one R group.

In certain embodiments (e.g., of Formula I or Formula II), R_(A) andR_(B) or R_(A1) and R_(B1) form a fused heteroaryl ring. In certainembodiments, the fused heteroaryl ring is pyrido or thieno. In certainembodiments, the fused heteroaryl ring is pyrido. In certain of theseembodiments, the pyrido ring is

wherein the highlighted bond indicates the position where the ring isfused.

In certain embodiments (e.g., of Formula I or Formula II), R_(A) andR_(B) or R_(A1) and R_(B1) form a fused 5 to 7 membered saturated ring.In certain embodiments, the ring is a cyclohexene ring.

In certain embodiments (e.g., of Formula I or Formula II), R_(A) andR_(B) or R_(A1) and R_(B1) form a fused 5 to 7 membered saturated ringcontaining one heteroatom selected from the group consisting of N and S.In certain embodiments, the ring is tetrahydropyrido or dihydrothieno.In certain embodiments the heteroatom is N. In certain embodiments, thering is tetrahydropyrido. In certain of these embodiments, the ring is

wherein the highlighted bond indicates the position where the ring isfused.

In certain embodiments (e.g., of Formula III), R_(A2) and R_(B2) areeach independently selected from the group consisting of hydrogen,halogen, alkyl, alkenyl, alkoxy, alkylthio, and —N(R₉)₂.

In certain embodiments (e.g., of Formula III), R_(A2) and R_(B2) areindependently hydrogen or alkyl.

In certain embodiments (e.g., of Formula III), R_(A2) and R_(B2) areboth methyl.

In certain embodiments (e.g., of any one of Formulas X through XIII), Ris selected from the group consisting of alkyl and haloalkyl.

In certain embodiments (e.g., including any one of the above embodimentsof Formulas I, II, IV through IX, XIV, XV, and XVI where R is present),R is selected from the group consisting of alkyl, alkoxy, halogen, andhydroxy.

In certain embodiments (e.g., including any one of the above embodimentsof Formulas I, II, IV through IX, XIV, XV, and XVI where R is present),R is hydroxy.

For certain embodiments (e.g., of Formulas IV or V), n is 0.

For certain embodiments (e.g., of Formula IV), n is 0 and m is 1.

For certain embodiments (e.g., of any one of Formulas VI through XIII),p is 0.

For certain embodiments (e.g., of any one of Formulas II, IV, VI throughIX, XIV, XV, and XVI), including any one of the above embodiments whichincludes R₃, R₃ is selected from the group consisting ofalkylsulfonylalkyleneoxy, alkylsulfonylaminoalkyleneoxy,alkylcarbonylaminoalkyleneoxy, aryl, arylalkyleneoxy, heteroaryl,heteroarylalkyleneoxy, heterocyclyl, heterocyclyloxy,heterocyclylalkyleneoxy, and heterocyclylcarbonylalkyleneoxy; whereinaryl and heteroaryl are unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,hydroxyalkyl, halogen, heterocyclylcarbonyl, and dialkylaminocarbonyl;and wherein heterocyclyl is unsubstituted or substituted by one or moresubstitutents selected from the group consisting of alkylsulfonyl,alkylcarbonyl, and oxo.

For certain embodiments (e.g., of any one of Formulas II, IV, VI throughIX, XIV, XV, and XVI), including any one of the above embodiments whichincludes R₃, R₃ is selected from the group consisting of benzyloxy,(4-chlorobenzyl)oxy, (4-methylbenzyl)oxy, phenyl, p-tolyl,2-ethoxyphenyl, 3-(morpholine-4-carbonyl)phenyl,3-(N,N-dimethylaminocarbonyl)phenyl, 3-furyl, pyridin-3-yl,pyridin-4-yl, 6-chloropyridin-3-yl, 6-fluoropyridin-3-yl,6-methylpyridin-3-yl, 5-(hydroxymethyl)pyridin-3-yl, and quinolin-3-yl.

For certain embodiments (e.g., of any one of Formulas II, IV, VI throughIX, XIV, XV, and XVI), including any one of the above embodiments whichincludes R₃, R₃ is selected from the group consisting of phenyl,p-tolyl, benzyloxy, (4-chlorobenzyl)oxy, (4-methylbenzyl)oxy, 3-furyl,pyridin-3-yl, 5-(hydroxymethyl)pyridin-3-yl, 6-chloropyridin-3-yl,6-fluoropyridin-3-yl, 6-methylpyridin-3-yl, 3-quinolin-3-yl, andthiazol-4-ylmethoxy.

For certain embodiments (e.g., of any one of Formulas II, IV, VI throughIX, XIV, XV, and XVI), including any one of the above embodiments whichincludes R₃, R₃ is pyridin-3-yl, pyridin-4-yl, 6-fluoropyridin-3-yl,5-(hydroxymethyl)pyridin-3-yl, quinolin-3-yl, 2-ethoxyphenyl, or3-(morpholine-4-carbonyl)phenyl.

For certain embodiments (e.g., of any one of Formulas II, IV, VI throughIX, XIV, XV, and XVI), including any one of the above embodiments whichincludes R₃, R₃ is 2-oxo-1,3-oxazolidin-3-yl.

For certain embodiments (e.g., of any one of Formulas II, IV, VI throughIX, XIV, XV, and XVI), including any one of the above embodiments whichincludes R₃, R₃ is 1,3-thiazol-4-ylmethoxy,(1-methyl-1H-imidazol-2-yl)methoxy, or pyridin-3-ylmethoxy.

For certain embodiments (e.g., of any one of Formulas II, IV, VI throughIX, XIV, XV, and XVI), including any one of the above embodiments whichincludes R₃, R₃ is 2-pyrrolidin-1-ylethoxy,2-(2-oxopyrrolidin-1-yl)ethoxy,2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy, 2-morpholin-4-ylethoxy,3-pyrrolidin-1-ylpropoxy, 3-(2-oxopyrrolidin-1-yl)propoxy,3-(1,1-dioxidoisothiazolidin-2-yl)propoxy, 3-morpholin-4-ylpropoxy,2-morpholin-4-yl-2-oxoethoxy, and

wherein R is alkylsulfonyl or alkylcarbonyl. For certain of theseembodiments, alkyl is methyl, ethyl, or isopropyl.

For certain embodiments (e.g., of any one of Formulas II, IV, VI throughIX, XIV, XV, and XVI), including any one of the above embodiments whichincludes R₃, R₃ is alkyl-S(O)₂—NH—(CH₂)₂₋₃—O—, alkyl-S(O)₂—(CH₂)₂₋₃—O—,or alkyl-C(O)—NH—(CH₂)₂₋₃—O—. For certain of these embodiments, alkyl ismethyl, ethyl, or isopropyl.

For certain embodiments (e.g., of any one of Formulas II, IV, VI throughIX, XIV, XV, and XVI), including any one of the above embodiments whichincludes R₃, R₃ is at the 7-position.

For certain embodiments (e.g., of any one of Formulas II, IV, VI throughIX, XIV, XV, and XVI), including any one of the above embodiments whichincludes R₃, R₃ is at the 8-position.

For certain embodiments (e.g., of any one of Formulas IV, VI throughIX), including any one of the above embodiments, m is 0.

For certain embodiments (e.g., of Formula IV), including any one of theabove embodiments of Formula IV, n is 0, and m is 0.

For certain embodiments (e.g., of any one of Formulas VI through IX),including any one of the above embodiments of Formulas VI through XI, pis 0, and m is 0.

For certain embodiments (e.g., of any one of Formulas I through XVI),including any one of the above embodiments, R₁ is R₄. For certain ofthese embodiments, R₄ is alkyl or arylalkylenyl. For certain of theseembodiments, R₄ is methyl, ethyl, n-propyl, 1-methylethyl, n-butyl,1-ethylpropyl, 2-methylpropyl, 3-methylbutyl, benzyl, 2-phenylethyl, or3-phenylpropyl.

For certain embodiments (e.g., of any one of Formulas I through XVI),including any one of the above embodiments, R₁ is —X—N(R₈)—Y—R₄. Forcertain of these embodiments, X is C₂₋₄ alkylene, R₈ is hydrogen, R₄ isC₁. alkyl, Y is —C(O)—, —S(O)₂—, or —C(O)—N(R₁₁)— wherein R₁₁ ishydrogen or R₁₁ and R₄ join to form a morpholine ring.

For certain embodiments, (e.g., of any one of Formulas XIV and XVI),including any one of the above embodiments of Formula XIV or XVI, X₁ isC₁₋₄ alkylene, and A₁ is —N(R₈)—, or —N(—Y—R₄)—. For certain of theseembodiments, A₁ is —N(R₈)—, For certain of these embodiments, R₈ ishydrogen, 2-hydroxyethyl, or benzyl. Alternatively, for certain of theseembodiments, A₁ is —N(—Y—R₄)—.

For certain embodiments, (e.g., of any one of Formulas XIV and XVI),including any one of the above embodiments of Formula XIV or XVI whereA₁ can be —N(—Y—R₄)—, X₁ is C₁₋₄ alkylene, and Y is —C(O)—, —S(O)₂—, or—C(O)—N(R₁₁)—. For certain of these embodiments, R₄ is C₁₋₆ alkyl, andR₁₁ is hydrogen or methyl. Alternatively, for certain of theseembodiments, Y is —C(O)—N(R₁₁)—, and R₄ and R₁₁ form the group

For certain of these embodiments, A is —CH₂— or —O—. For certain ofthese embodiments, a and b are each independently 1 or 2, with theproviso that when A is —O— then a and b are each 2.

For certain embodiments (e.g., of any one of Formulas I through XVI),including any one of the above embodiments, R₁′ is hydrogen.

For certain embodiments (e.g., of any one of Formulas II through XVI),including any one of the above embodiments, R₂ is hydrogen, alkyl,alkoxyalkylenyl, or hydroxyalkylenyl.

For certain embodiments (e.g., of any one of Formulas II through XVI),including any one of the above embodiments, R₂ is C₁₋₄alkyl,C₁₋₄alkyl-O—C₂₋₄ alkylenyl, or hydroxyC₂₋₄ alkylenyl.

For certain embodiments (e.g., of any one of Formulas II through XVI),including any one of the above embodiments, R₂ is methyl, ethyl,n-propyl, n-butyl, 2-methoxyethyl, or 2-hydroxyethyl.

For certain embodiments, R₁ alkyl or arylalkylenyl.

For certain embodiments, R₁ is methyl, ethyl, n-propyl, 1-methylethyl,n-butyl, 1-ethylpropyl, 2-methylpropyl, 3-methylbutyl, benzyl,2-phenylethyl, or 3-phenylpropyl.

For certain embodiments, R₁ is —X—N(R₈)—Y—R₄.

For certain embodiments, R₁′ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl wherein thealkylenyl group contains at least two carbon atoms between the hydroxyor alkoxy substituent and the nitrogen atom to which R₁′ is bonded;

or R₁ and R₁′ together with the nitrogen atom to which they are bondedcan join to form a group selected from the group consisting of:

For certain embodiments, R₁ is hydrogen.

For certain embodiments, R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclylwherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclylgroups can be unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, alkoxy,haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano,carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy,heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino,alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case ofalkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso thatwhen R₁ is R₄, and R₄ is a substituted alkyl group, and the substituentcontains a hetero atom which bonds directly to the alkyl group, then thealkyl group contains at least two carbons between the substituent andthe nitrogen atom to which R₁ is bonded.

For certain embodiments, R₄ is aryl, heteroaryl, or heterocyclyl.

For certain embodiments, R₄ is alkyl, aryl, or heteroaryl.

For certain embodiments, R₄ is alkyl or arylalkylenyl.

For certain embodiments, R₄ is C₁₋₆alkyl.

For certain embodiments, R₄ is aryl.

For certain embodiments, R₄ is heteroaryl.

For certain embodiments, R₄′ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

For certain embodiments, R₄′ is aryl, heteroaryl, or heterocyclyl.

For certain embodiments, R₄′ is alkyl, aryl, or heteroaryl.

For certain embodiments, R₄′ is alkyl.

For certain embodiments, R₄′ is aryl.

For certain embodiments, R₄′ is heteroaryl.

For certain embodiments, R₅ is selected from the group consisting of:

For certain embodiments, R₅′ is selected from the group consisting of:

For certain embodiments, R₅′ is selected from the group consisting of

For certain embodiments, R₅′ is selected from the group consisting of

For certain embodiments, R₆ is selected from the group consisting of ═Oand ═S.

For certain embodiments, R₆ is ═O.

For certain embodiments, R₆ is ═S.

For certain embodiments, R₇ is C₂₋₇ alkylene.

For certain embodiments, R₇ is C₃₋₄ alkylene.

For certain embodiments, R₈ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl.

For certain embodiments, R₈ is hydrogen.

For certain embodiments, R₈ is alkyl.

For certain embodiments, R₈ is hydrogen, 2-hydroxyethyl, or benzyl.

For certain embodiments, R₈ is 2-hydroxyethyl.

For certain embodiments, R₈ is benzyl.

For certain embodiments, R₉ is selected from the group consisting ofhydrogen and alkyl.

For certain embodiments, R₉ is alkyl.

For certain embodiments, R₉ is hydrogen.

For certain embodiments, R₁₀ is C₃₋₈ alkylene.

For certain embodiments, R₁₀ is C₄₋₅ alkylene.

For certain embodiments, R₁₁ is hydrogen or methyl.

For certain embodiments, R₁₁ is hydrogen.

For certain embodiments, R₄ and R₁₁ form the group

wherein A is —CH₂— or —O—, and a and b are each independently 1 or 2,with the proviso that when A is —O— then a and b are each 2.

For certain of these embodiments, R₁₁ and R₄ join to form a morpholinering.

For certain of these embodiments, R₁₁ and R₄ join to form a 4 to 6membered ring.

For certain of these embodiments, R₁₁ and R₄ join to form a pyrrolidinering.

For certain of these embodiments, R₁₁ and R₄ join to form a piperidinering.

For certain embodiments, A is selected from the group consisting of—CH(R₈)—, —O—, —N(R₈)—, —N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—.

For certain embodiments, A is selected from the group consisting of—CH(R₈)—, —O—, and —N(R₈)—.

For certain embodiments, A₁ is —CH₂— or —O—.

For certain embodiments, A is —O—.

For certain embodiments, A₁ is selected from the group consisting of—N(R₈)— and —N(—Y—R₄)—.

For certain embodiments, A₁ is —N(R₈)—.

For certain embodiments, A₁ is —N(—Y—R₄)—.

For certain embodiments, A′ is selected from the group consisting of—O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—.

For certain embodiments, A′ is —O—.

For certain embodiments, A″ is selected from the group consisting of—O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—.

For certain embodiments, including any one of the above embodiments ofFormula XV or XVI, G is selected from the group consisting of —C(O)—R′″,α-aminoacyl, and —C(O)—O—R′″. For certain of these embodiments, R′″contains one to ten carbon atoms. For certain of these embodiments,α-aminoacyl is an α-C₂₋₁₁ aminoacyl group derived from an α-amino acidselected from the group consisting of racemic, D-, and L-amino acidscontaining a total of at least 2 carbon atoms and a total of up to 11carbon atoms, and may also include one or more heteroatoms selected fromthe group consisting of O, S, and N.

For certain embodiments, including any one of the above embodimentswhich include an α-aminoacyl group, α-aminoacyl is an α-aminoacyl groupderived from a naturally occurring α-amino acid selected from the groupconsisting of racemic, D-, and L-amino acids.

For certain embodiments, including any one of the above embodimentswhich include an α-aminoacyl group, α-aminoacyl is an α-aminoacyl groupderived from an α-amino acid found in proteins, wherein the amino acidis selected from the group consisting of racemic, D-, and L-amino acids.

For certain embodiments, Q is selected from the group consisting of abond, —C(R₆)—, —C(R₆)—C(R₆)—, —S(O—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,—C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—.

For certain embodiments, Q is a bond, —C(R₆)—, —S(O)—, or—C(R₆)—N(R₈)—W—.

For certain embodiments, Q is a bond.

For certain embodiments, V is selected from the group consisting of—C(R₆)—, —O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—.

For certain embodiments, V is —C(R₆)—.

For certain embodiments, V is —N(R₈)—C(R₆)—.

For certain embodiments, W is selected from the group consisting of abond, —C(O)—, and —S(O)₂—.

For certain embodiments, W is selected from the group consisting of abond and —C(O)—.

For certain embodiments, W is a bond.

For certain embodiments, X is C₂₋₂₀ alkylene.

For certain embodiments, X is C₂₋₄ alkylene.

X′ is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated by arylene, heteroarylene or heterocyclyleneand optionally interrupted by one or more —O— groups.

For certain embodiments, X′ is C₁₋₄ alkylene.

For certain embodiments, X₁ is C₁₋₄ alkylene.

For certain embodiments, X₁ is methylene or ethylene.

For certain embodiments, Y is selected from the group consisting of—C(R₆)—, —C(R₆)—O—, —S(O)₂—, —S(O)₂—N(R₈)—, and —C(R₆)—N(R₁₁)—; whereinR₁₁ is selected from the group consisting of hydrogen, alkyl, andarylalkylenyl; or R₁₁ and R₄ together with the nitrogen atom to whichR₁₁ is bonded can join to form the group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4.

For certain embodiments, Y is —C(O)—, —S(O)₂—, or —C(O)—N(R₁₁)—. Forcertain of these embodiments, R₁₁ is hydrogen. For certain of theseembodiments, R₁₁ and R₄ join to form a morpholine ring.

For certain embodiments, Y′ is selected from the group consisting of—O—, —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—,—O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,—O—N(R₈)-Q-, —O—N═C(R₆)—, —C(═N—O—R₈)—, —CH(—N(—O—R₈)-Q-R₄)—,

For certain embodiments, Y′ is —C(O)—, —S(O)₂—, —NH—S(O)₂—, or—NH—C(O)—.

For certain embodiments, Y is —S(O)₂—, —NH—S(O)₂—, or —NH—C(O)—.

For certain embodiments, Z is a bond or —O—.

For certain embodiments, a and b are independently integers from 1 to 4with the proviso that when A is —O—, —N(R₈)—, —N(Y—R₄)—, or—N(X—N(R₈)—Y—R₄)— then a and b are independently integers from 2 to 4.

For certain embodiments, a and b are each independently 1 or 2, with theproviso that when A is —O— then a and b are each 2.

For certain embodiments, c and d are independently integers from 1 to 6with the proviso that c+d is ≦7. For certain embodiments, c and d areeach the integer 2.

For certain embodiments, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor salt of any one of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X,XI, XII, XIII, XIV, XV, XVI, or any one of the above embodiments incombination with a pharmaceutically acceptable carrier.

For certain embodiments, the present invention provides a method ofinducing cytokine biosynthesis in an animal comprising administering aneffective amount of a compound or salt of any one of Formulas I, II,III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or anyone of the above embodiments or administering any one of the abovepharmaceutical compositions to the animal. For certain of theseembodiments, the cytokine is selected from the group consisting ofIFN-α, TNF-α, IL-6, IL-10, and IL-12. For certain of these embodiments,the cytokine is IFN-α or TNF-α.

For certain embodiments, the present invention provides a method oftreating a viral disease in an animal comprising administering atherapeutically effective amount of a compound or salt of any one ofFormulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV,XV, XVI, or any one of the above embodiments or administering any one ofthe above pharmaceutical compositions to the animal.

For certain embodiments, the present invention provides a method oftreating a neoplastic disease in an animal comprising administering atherapeutically effective amount of a compound or salt of any one ofFormulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV,XV, XVI, or any one of the above embodiments or administering any one ofthe above pharmaceutical compositions to the animal.

Preparation of the Compounds

Compounds of the invention may be synthesized by synthetic routes thatinclude processes analogous to those well known in the chemical arts,particularly in light of the description contained herein. The startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis., USA) or are readily prepared usingmethods well known to those skilled in the art (e.g. prepared by methodsgenerally described in Louis F. Fieser and Mary Fieser, Reagents forOrganic Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.); Alan R.Katritsky, Otto Meth-Cohn, Charles W. Rees, Comprehensive OrganicFunctional Group Transformations, v 1-6, Pergamon Press, Oxford,England, (1995); Barry M. Trost and Ian Fleming, Comprehensive OrganicSynthesis, v. 1-8, Pergamon Press, Oxford, England, (1991); orBeilsteins Handbuch der organischen Chemie, 4, Aufl. Ed.Springer-Verlag, Berlin, Germany, including supplements (also availablevia the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as key intermediates. For more detailed description of theindividual reaction steps, see the EXAMPLES section below. Those skilledin the art will appreciate that other synthetic routes may be used tosynthesize the compounds of the invention. Although specific startingmaterials and reagents are depicted in the reaction schemes anddiscussed below, other starting materials and reagents can be easilysubstituted to provide a variety of derivatives and/or reactionconditions. In addition, many of the compounds prepared by the methodsdescribed below can be further modified in light of this disclosureusing conventional methods well known to those skilled in the art.

In the preparation of compounds of the invention it may sometimes benecessary to protect a particular functionality while reacting otherfunctional groups on an intermediate. The need for such protection willvary depending on the nature of the particular functional group and theconditions of the reaction step. Suitable amino protecting groupsinclude acetyl, trifluoroacetyl, tert-butxoycarbonyl (Boc),benzyloxycarbonyl, and 9-fluorenylmethyleneoxycarbonyl. Suitable hydroxyprotecting groups include acetyl and silyl groups such as the tert-butyldimethylsilyl group. For a general description of protecting groups andtheir use, see T. W. Greene, Protective Groups in Organic Synthesis,John Wiley & Sons, New York, USA, 1991.

Conventional methods and techniques of separation and purification canbe used to isolate compounds of the invention, as well as variousintermediates related thereto. Such techniques may include, for example,all types of chromatography (high performance liquid chromatography(HPLC), column chromatography using common absorbents such as silicagel, and thin layer chromatography), recrystallization, and differential(i.e., liquid-liquid) extraction techniques.

In some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme I where R, R₁, R₂, and n are as definedabove.

In step (1) of Reaction Scheme I, a 2-aminophenylacetonitrile of FormulaXX is reacted with acetonylacetone to provide a substituted2,5-dimethylpyrrole of Formula XXI. The reaction can be carried out bycombining a 2-aminophenylacetonitrile of Formula XX with acetonylacetonealong with a catalytic amount of p-toluenesulfonic acid in a suitablesolvent such as toluene. The reaction can be heated at an elevatedtemperature such as at the reflux temperature.

In step (2) of Reaction Scheme I, a substituted 2,5-dimethylpyrrole ofFormula XXI is acylated to provide an oxalated compound of Formula XXII.The acylation can be carried out by adding a compound of Formula XXI anddiethyl oxalate to a solution of sodium tert-butoxide in a suitablesolvent such as ethanol and then heating at reflux under an inertatmosphere.

In step (3) of Reaction Scheme I, an oxalated compound of Formula XXIIis reacted with a hydrazine of the Formula R₂NHNH₂ to provide apyrazolo[3,4-c]quinolin-1-amine of Formula XXIII. The reaction can becarried out by adding a solution of the hydrazine in acetic acid to asolution of a compound of Formula XXII in a suitable solvent such asethanol. The reaction can be carried out at an elevated temperature suchas the reflux temperature of the solvent.

In step (4) of Reaction Scheme I, a pyrazolo[3,4-c]quinolin-1-amine ofFormula XXIII is chlorinated to provide a4-chloropyrazolo[3,4-c]quinolin-1-amine of Formula XXIV. The reactioncan be carried out by combining a compound of Formula XXIII withphosphorus oxychloride and heating.

In step (5a) of Reaction Scheme I,4-chloropyrazolo[3,4-c]quinolin-1-amine of Formula XXIV or a saltthereof is treated with a ketone, aldehyde, or corresponding ketal oracetal thereof, under acidic conditions to provide a4-chloropyrazolo[3,4-c]quinolin-1-imine of Formula XXV. For example, aketone is added to a solution of the hydrochloride salt of a compound ofFormula XXIV in a suitable solvent such as isopropanol in the presenceof an acid or acid resin, for example, DOWEX W50-X1 acid resin. Theketone, aldehyde, or corresponding ketal or acetal, is selected with R₁and R₁₁ groups that will provide the desired R₁ substituent. Forexample, acetone will provide a compound where R₁ is isopropyl, andbenzaldehyde will provide a compound where R₁ is benzyl. The reaction isrun with sufficient heating to drive off the water formed as a byproductof the reaction.

In step (6) of Reaction Scheme I, a4-chloropyrazolo[3,4-c]quinolin-1-imine of Formula XXV is reduced toprovide a 4-chloropyrazolo[3,4-c]quinolin-1-amine of Formula XXVI. Thereaction can be carried out by adding sodium borohydride to a solutionof a compound of Formula XXV in a suitable solvent such as methanol atambient temperature.

Alternatively, in step (5b) of Reaction Scheme I, a4-chloropyrazolo[3,4-c]quinolin-1-amine of Formula XXIV can be treatedwith a ketone and a borohydride under acidic conditions to provide a4-chloropyrazolo[3,4-c]quinolin-1-amine of Formula XXVI. The reactioncan be carried out at ambient temperature in a suitable solvent such as1,2-dichloroethane.

Steps (5) and (6) are omitted for compounds where R₁ is hydrogen.

In step (7) of Reaction Scheme I, the chloro group of apyrazolo[3,4-c]quinolin-1-amine of Formula XXVI is displaced to providea pyrazolo[3,4-c]quinolin-1,4-diamine of Formula IVa, which is asubgenus of Formulas I, II, and IV. The reaction can be carried out bycombining a compound of Formula XXVI with a solution of ammonia inmethanol and heating the mixture in a sealed reactor.

In some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme II where R₁, R₁′, R₂, and n are as definedabove and R_(a) is a subset of R that does not include halogen oralkenyl.

In step (1) of Reaction Scheme II, an indole of Formula XXVII isacylated to provide an oxalated indole of Formula XXVIII. The reactioncan be carried out by adding ethyl chlorooxoacetate to a solution of anindole of Formula XXVII in a suitable solvent such as diethyl ether inthe presence of pyridine. The reaction can be carried out at asub-ambient temperature such as 0° C. Many indoles of Formula XXVII areknown. Some are commercially available and others can be readilyprepared using known synthetic methods.

In step (2) of Reaction Scheme II, an oxalated indole of Formula XXVIIIis rearranged to a pyrazolo[3,4-c]quinolin-4-one of Formula XXIX. Thereaction can be carried out by adding a hydrazine of Formula R₂NHNH₂ toa solution of an oxalated indole of Formula XXVIII in a solvent orsolvent mix such as ethanol/acetic acid in the presence of hydrochloricacid. The reaction can be carried out at an elevated temperature such asat reflux.

If step (2) is carried out using hydrazine, the resultingpyrazolo[3,4-c]quinolin-4-one of Formula XXIX where R₂ is hydrogen canbe further elaborated using known synthetic methods. For example, apyrazolo[3,4-c]quinolin-4-one of Formula XXIX where R₂ is hydrogen canbe alkylated. The alkylation can be carried out by treating a solutionof a pyrazolo[3,4-c]quinolin-4-one of Formula XXIX, where R₂ ishydrogen, with a base such as sodium ethoxide followed by the additionof an alkyl halide. The reaction can be run in a suitable solvent suchas ethanol and can be carried out at an elevated temperature, forexample, the reflux temperature of the solvent, or at ambienttemperature. Alternatively, a pyrazolo[3,4-c]quinolin-4-one of FormulaXXIX where R₂ is hydrogen can undergo a Buchwald amination with an arylhalide or heteroaryl halide. Numerous alkyl halides, aryl halides, andheteroaryl halides are commercially available; others can be preparedusing known synthetic methods.

Step (2) can also be carried out using a hydrazine that will install aremovable group at R₂. Examples of such hydrazines includebenzylhydrazine and tert-butylhydrazine. At a later point in thesynthetic pathway the group can be removed using conventional methods toprovide a compound in which R₂ is hydrogen. The compound may then befurther elaborated using the methods described above.

In step (3) of Reaction Scheme II, a pyrazolo[3,4-c]quinolin-4-one ofFormula XXIX is halogenated using conventional methods. The reaction canbe carried out by deprotonating a compound of Formula XXIX with n-butyllithium and then adding iodine.

In step (4) of Reaction Scheme II, the halogen group on apyrazolo[3,4-c]quinolin-4-one of Formula XXX is displaced with an amineof Formula HN(R₁)(R₁′). Either thermal or catalytic, using palladium forexample, displacement methods can be used.

Steps (5) and (6) can be carried out using the methods of steps (4) and(7) respectively of Reaction Scheme I to provide a provide apyrazolo[3,4-c]quinolin-1,4-diamine of Formula IVb, which is a subgenusof Formulas I, II, and IV.

In some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme III where R_(a), R₁, R₂, and n are asdefined above.

In step (1) of Reaction Scheme III, a carboxyl group is installed on apyrazolo[3,4-c]quinolin-4-one of Formula XXIX. The reaction can becarried out by deprotonating a compound of Formula XXIX with n-butyllithium and then quenching with carbon dioxide.

In step (2) of Reaction Scheme III, a pyrazolo[3,4-c]quinolin-4-one ofFormula XXIII is treated with diphenyl phosphoryl azide to provide apyrazolo[3,4-c]quinolin-1-amine of Formula XXIII.

The remaining steps can be carried out using the methods of steps (4)through (7) of Reaction Scheme I to provide apyrazolo[3,4-c]quinolin-1,4-diamine of Formula IVc.

For some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme IV, wherein R₁, R₁′, and R₂ are defined asabove and R_(3b) and R_(3c) are defined below, and R_(4a) methyl orbenzyl.

Steps (1) through (6) of Reaction Scheme IV can be carried out asdescribed for steps (1) through (6) of Reaction Scheme II. Somebenzyloxy-substituted indoles and methoxy-substituted indoles of FormulaXXXIV are known; others can be prepared using known synthetic methods.

In step (7) of Reaction Scheme IV, the benzyl or methyl group ofpyrazolo[3,4-c]quinoline of Formula IVd, which is a subgenus of FormulaIV, is cleaved using conventional methods to providepyrazolo[3,4-c]quinolinol of Formula IVe, which is a subgenus of FormulaIV. Cleavage of the benzyl group can be carried out on a Parr apparatusunder hydrogenolysis conditions using a suitable heterogeneous catalystsuch as palladium on carbon in a solvent such as ethanol. Alternatively,the reaction can be carried out by transfer hydrogenation in thepresence of a suitable hydrogenation catalyst. The transferhydrogenation can be carried out by adding ammonium formate to asolution of a pyrazolo[3,4-c]quinoline of Formula IVd in a suitablesolvent such as ethanol in the presence of a catalyst such as palladiumon carbon. The reaction can be carried out at an elevated temperature,for example, the reflux temperature of the solvent. Demethylation can becarried out by treating a pyrazolo[3,4-c]quinoline of Formula IVd with asolution of boron tribromide in a suitable solvent such asdichloromethane. The reaction can be carried out at a sub-ambienttemperature such as 0° C. Alternatively, the demethylation can becarried out by heating a pyrazolo[3,4-c]quinoline of Formula IVd withanhydrous pyridinium chloride at an elevated temperature, such as 210°C.

In step (8a) of Reaction Scheme IV, the hydroxy group of apyrazolo[3,4-c]quinolinol of Formula IVe is activated by conversion to atrifluoromethanesulfonate (triflate) group. The reaction can be carriedout by treating a pyrazolo[3,4-c]quinolinol of Formula IVe withN-phenyl-bis(trifluoromethanesulfonamide) in the presence of a tertiaryamine such as triethylamine. The reaction can be carried out at ambienttemperature in a suitable solvent such as DMF.

Step (9) of Reaction Scheme IV can be carried out using knownpalladium-catalyzed coupling reactions such as the Suzuki coupling, Heckreaction, the Stille coupling, and the Sonogashira coupling. Forexample, a triflate-substituted pyrazolo[3,4-c]quinoline of Formula XXXVundergoes Suzuki coupling with a boronic acid of Formula R_(3b)—B(OH)₂,an anhydride thereof, or a boronic acid ester of FormulaR_(3b)—B(O-alkyl)₂; wherein R_(3b) is —R_(4b), —X_(e)—R₄, —X_(f)—Y—R₄,or —X_(f)—R₅; where X_(e) is alkenylene; X_(f) is arylene,heteroarylene, and alkenylene interrupted or terminated by arylene orheteroarylene; R_(4b) is aryl or heteroaryl where the aryl or heteroarylgroups can be unsubstituted or substituted as defined in R₄ above; andR₄, R₅, and Y are as defined above. The coupling can be carried out bycombining a triflate-substituted pyrazolo[3,4-c]quinoline of FormulaXXXV with a boronic acid or an ester or anhydride thereof in thepresence of palladium (II) acetate, triphenylphosphine, and a base suchas aqueous sodium carbonate in a suitable solvent such as n-propanol.The reaction can be carried out at an elevated temperature, for example,at the reflux temperature. Numerous boronic acids of FormulaR_(3b)—B(OH)₂, anhydrides thereof, and boronic acid esters of FormulaR_(3b)—B(O-alkyl)₂ are commercially available; others can be readilyprepared using known synthetic methods.

Alternatively, the Heck reaction can be used in step (9) of ReactionScheme IV to provide compounds of Formula IVg, wherein R_(3b) is—X_(e)—R_(4b) or —X_(e)—Y—R₄, wherein X_(e), Y, R₄, and R_(4b) are asdefined above. The Heck reaction can be carried out by coupling atriflate-substituted pyrazolo[3,4-c]quinoline of Formula XXXV with acompound of the Formula H₂C═C(H)—R_(4b) or H₂C═C(H)—Y—R₄. Several ofthese vinyl-substituted compounds are commercially available; others canbe prepared by known methods. The reaction can be carried out bycombining a triflate-substituted pyrazolo[3,4-c]quinoline of FormulaXXXV and the vinyl-substituted compound in the presence of palladium(II) acetate, triphenylphosphine or tri-ortho-tolylphosphine, and a basesuch as triethylamine in a suitable solvent such as acetonitrile ortoluene. The reaction can be carried out at an elevated temperature suchas 100-120° C. under an inert atmosphere.

Compounds of Formula IVg, wherein R_(3b) is —X_(g)—R₄, X_(g) isalkynylene, and R₄ is as defined above, can also be prepared bypalladium catalyzed coupling reactions such as the Stille coupling orSonogashira coupling. These reactions are carried out by coupling atriflate-substituted pyrazolo[3,4-c]quinoline of Formula XXXV with acompound of the Formula (alkyl)₃Sn—C≡C—R₄, (alkyl)₃Si—C≡C—R₄, orH—C≡C—R₄.

Compounds of Formula IVg prepared as described above bypalladium-mediated coupling reactions, wherein R_(3b) is —X_(e)—R₄,—X_(e)—Y—R₄, —X_(f2)—Y—R₄, —X_(f2)—R₅, or —X_(g)—R₄, where X_(f2) isalkenylene interrupted or terminated by arylene or heteroarylene, andX_(e), X_(g), Y, R₄, and R₅ are as defined above, can undergo reductionof the alkenylene or alkynylene group present to providepyrazolo[3,4-c]quinolines of Formula IVg wherein R_(3b) is —X_(h)—R₄,—X_(h)—Y—R₄, —X_(i)—Y—R₄, or —X₁—R₅, where X_(h) is alkylene; X_(i) isalkylene interrupted or terminated by arylene or heteroarylene; and R₄,R₅, and Y are as defined above. The reduction can be carried out byhydrogenation using a conventional heterogeneous hydrogenation catalystsuch as palladium on carbon. The reaction can be carried out on a Parrapparatus in a suitable solvent such as ethanol, methanol, or mixturesthereof.

In step (8b) of Reaction Scheme IV, a pyrazolo[3,4-c]quinolinol ofFormula IVe is converted to a pyrazolo[3,4-c]quinoline of Formula IVf,wherein R_(3c) is —O—R₄, —O—X—R₄, —O—X—Y—R₄, or —O—X—R₅, and X, Y, R₄,and R₅ are as defined above, using a Williamson-type ether synthesis.The reaction can be effected by treating a pyrazolo[3,4-c]quinolinol ofFormula IVe with an aryl, alkyl, or arylalkylenyl halide of FormulaHalide-R₄, Halide-alkylene-R₄, Halide-alkylene-Y—R₄, orHalide-alkylene-R₅ in the presence of a base. Numerous alkyl,arylalkylenyl, and aryl halides of these formulas are commerciallyavailable, including substituted benzyl bromides and chlorides,substituted or unsubstituted alkyl or arylalkylenyl bromides andchlorides, bromo-substituted ketones, esters, and heterocycles, andsubstituted fluorobenzenes. Other halides of these formulas can beprepared using conventional synthetic methods. The reaction can becarried out by combining an alkyl, arylalkylenyl, or aryl halide with apyrazolo[3,4-c]quinolinol of Formula IVe in a solvent such as DMF orN,N-dimethylacetamide in the presence of a suitable base such as cesiumcarbonate. Optionally, catalytic tetrabutylammonium bromide can beadded. The reaction can be carried out at ambient temperature or at anelevated temperature, for example 50° C. or 85° C., depending on thereactivity of the halide reagent.

Alternatively, step (8b) may be carried out using the Ullmann ethersynthesis, in which an alkali metal aryloxide prepared from apyrazolo[3,4-c]quinolinol of Formula IVe reacts with an aryl halide inthe presence of copper salts, to provide a pyrazolo[3,4-c]quinoline ofFormula IVe, where R_(3c) is —O—R_(4b), —O—X_(j)—R₄, or —O—X_(j)—Y—R₄,wherein X_(j) is an arylene or heteroarylene and R_(4b) is as definedabove. Numerous substituted and unsubstituted aryl halides arecommercially available; others can be prepared using conventionalmethods.

The methods described in steps (7) through (9) and (7) through (8b) canalso be used to install R_(3b) or R_(3c) groups at an earlier stage inthe synthetic pathway.

For some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme V, where R_(b), R_(1b), and R_(2b) aresubsets of R, R₁, and R₂ as defined above that do not include thosesubstituents which would be susceptible to reduction under the acidichydrogenation conditions of the reaction and n is as defined above.

In Reaction Scheme V, a pyrazolo[3,4-c]quinoline of Formula IVh isreduced to provide a 6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinoline ofFormula Va, which is a subgenus of Formulas I, II, and V. The reactionmay be carried out under heterogeneous hydrogenation conditions byadding platinum (IV) oxide to a solution or suspension of apyrazolo[3,4-c]quinoline of Formula IVh in a suitable solvent such astrifluoroacetic acid and placing the reaction under hydrogen pressure.

Alternatively, the reduction may be carried out at an earlier stage inthe synthetic pathway.

Pyrazolo[3,4-c]naphthyridines of the invention can be prepared by usingan azaindole as the starting material in Reaction Schemes II and IV.Azaindoles are known compounds. Some are commercially available andothers can be prepared using known synthetic methods. Alternatively,pyrazolo[3,4-c]naphthyridines of the invention can be prepared by usinga 2-aminopyridinylaceotonitrile as the starting material in ReactionScheme I.

6,7,8,9-Tetrahydro-2H-pyrazolo[3,4-c]naphthyridines can be prepared byreducing pyrazolo[3,4-c]naphthyridines using the method of ReactionScheme V.

For some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme VI where R_(a), R₁, R₂, and n are asdefined above.

In step (1) of Reaction Scheme VI, a pyrazolo[3,4-c]quinolin-4-one ofFormula XXXIII is chlorinated to provide a4-chloropyrazolo[3,4-c]quinoline-1-carbonyl chloride of Formula XXXVI.The reaction can be carried out by combining a compound of FormulaXXXIII with an excess of thionyl chloride in a suitable solvent such astoluene and heating at an elevated temperature such as, for example, thereflux temperature of the solvent.

In step (2) of Reaction Scheme VI, a4-chloropyrazolo[3,4-c]quinoline-1-carbonyl chloride of Formula XXXVI isreacted with sodium azide to provide a4-chloropyrazolo[3,4-c]quinoline-1-carbonyl azide of Formula XXXVII. Thereaction can be carried out by treating a solution of a compound ofFormula XXXVI in a suitable solvent such as acetone with a solution ofsodium azide in water. The reaction can be carried out at a sub-ambienttemperature such as, for example, 0° C.

In step (3) of Reaction Scheme VI, a4-chloropyrazolo[3,4-c]quinoline-1-carbonyl azide of Formula XXXVIIundergoes a Curtius rearrangement in the presence of tert-butanol toprovide a tert-butyl 4-chloropyrazolo[3,4-c]quinolin-1-ylcarbamate ofFormula XXVIII. The reaction can be carried out by combing a compound ofFormula XXXVII with an excess of tert-butanol in a suitable solvent suchas toluene and heating at an elevated temperature such as, for example,the reflux temperature of the solvent.

In step (4) of Reaction Scheme VI, a tert-butyl4-chloropyrazolo[3,4-c]quinolin-1-ylcarbamate of Formula XXXVIII isreacted with an iodide of Formula I-R₁ to provide a tert-butyl4-chloropyrazolo[3,4-c]quinolin-1-ylcarbamate of Formula XXXIX. Thereaction can be carried out by treating a solution of a compound ofXXXVIII and an iodide of Formula I-R₁ in a suitable solvent such astetrahydrofuran with sodium hydride. The reaction can be carried out atambient temperature.

In step (5) of Reaction Scheme VI, the chloro group of a tert-butyl4-chloropyrazolo[3,4-c]quinolin-1-ylcarbamate of Formula XXXIX isdisplaced and the Boc group is removed to provide apyrazolo[3,4-c]quinolin-4-amine of Formula IVc. The reaction can becarried out by combining a compound of Formula XXXIX with a solution ofammonia in methanol in a pressure vessel and heating at an elevatedtemperature such as 150° C.

For some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme VII where R_(a), R₁, R₂, R₄, R₈, Y, and nare as defined above, Boc is tert-butoxycarbonyl, and X_(1a) isC₁₋₄alkylene.

In step (1) of Reaction Scheme VII, a tert-butyl4-chloropyrazolo[3,4-c]quinolin-1-ylcarbamate of Formula XXXVIII isreacted with a Boc protected 4-(iodoalkyl)piperidine of Formula XL toprovide a tert-butyl 4-chloropyrazolo[3,4-c]quinolin-1-ylcarbamate ofFormula XLI. The reaction can be carried out as described in step (4) ofReaction Scheme VI.

In step (2) of Reaction Scheme VII, the chloro group of a tert-butyl4-chloropyrazolo[3,4-c]quinolin-1-ylcarbamate of Formula XLI isdisplaced and one of the Boc groups is removed to provide apyrazolo[3,4-c]quinolin-4-amine of Formula XIVa. The reaction can becarried out as described in step (5) of Reaction Scheme VI.

In step (3) of Reaction Scheme VII, the Boc group is removed from apyrazolo[3,4-c]quinolin-4-amine of Formula XIVa to provide apyrazolo[3,4-c]quinolin-4-amine of Formula XIVb. The reaction can becarried out by treating a solution or suspension of a compound ofFormula XIVa in a suitable solvent such as ethanol with a strong acidsuch as hydrochloric acid. The reaction can be run at an elevatedtemperature such as, for example, the reflux temperature of the solvent.

In step (4a) of Reaction Scheme VII, the piperidinyl group in apyrazolo[3,4-c]quinolin-4-amine of Formula XIVb is further elaboratedusing conventional methods to provide pyrazolo[3,4-c]quinolin-4-amine ofFormula XIVc. For example, a compound of Formula XIVb or a salt thereofcan react with an acid chloride of Formula R₄C(O)Cl to provide acompound of Formula XIVc in which Y is —C(O)—. In addition, a compoundof Formula XIVb can react with a sulfonyl chloride of Formula R₄S(O)₂Clor a sulfonic anhydride of Formula (R₄S(O)₂)₂O to provide a compound ofFormula XIVc in which Y is —S(O)₂—. Numerous acid chlorides of FormulaR₄C(O)Cl, sulfonyl chlorides of Formula R₄S(O)₂Cl, and sulfonicanhydrides of Formula (R₄S(O)₂)₂O are commercially available; others canbe readily prepared using known synthetic methods. The reaction can becarried out by adding the acid chloride of Formula R₄C(O)Cl, sulfonylchloride of Formula R₄S(O)₂Cl, or sulfonic anhydride of Formula(R₄S(O)₂)₂O to a solution or suspension of a compound of Formula XIVb ina suitable solvent such as chloroform, dichloromethane,N,N-dimethylacetamide (DMA), or N,N-dimethylformamide (DMF). Optionallya base such as triethylamine or N,N-diisopropylethylamine can be added.The reaction can be carried out at ambient temperature or at asub-ambient temperature such as 0° C.

Ureas of Formula XIVc, where Y is —C(O)—NH— can be prepared by reactinga compound of Formula XIVb or a salt thereof with isocyanates of FormulaR₄N═C═O, Numerous isocyanates of Formula R₄N═C═O are commerciallyavailable; others can be readily prepared using known synthetic methods.The reaction can be carried out by adding the isocyanate of FormulaR₄N═C═O to a solution or suspension of a compound of Formula XIVb in asuitable solvent such as DMA, DMF, or chloroform. Optionally a base suchas triethylamine or N,N-diisopropylethylamine can be added. The reactioncan be carried out at ambient temperature or a sub-ambient temperaturesuch as 0° C. Alternatively, a compound of Formula XIVb can be treatedwith a carbamoyl chloride of Formula Cl—C(O)-heterocyclyl, whereinheterocyclyl is attached at a nitrogen atom, to provide a compound ofFormula XIVc, wherein Y is —C(O)— and R₄ is heterocyclyl attached at anitrogen atom.

Sulfamides of Formula XIVc, where Y is —S(O)₂—N(R₈)—, can be prepared byreacting a compound or salt of Formula XIVb with sulfuryl chloride togenerate a sulfamoyl chloride in situ, and then reacting the sulfamoylchloride with an amine of Formula HN(R₈)R₄. Alternatively, sulfamides ofFormula XIVc can be prepared by reacting a compound of Formula XIvb witha sulfamoyl chloride of Formula R₄(R₈)N—S(O)₂Cl. Many sulfonyl chloridesof Formula R₄S(O)₂Cl and amines of Formula HN(R₈)R₄, and some sulfamoylchlorides of Formula R₄(R₈)N—S(O)₂Cl are commercially available; otherscan be prepared using known synthetic methods.

In step (4b) of Reaction Scheme VII, a pyrazolo[3,4-c]quinolin-4-amineof Formula XIVb undergoes reductive alkylation to provide apyrazolo[3,4-c]quinolin-4-amine of Formula XIVd. The alkylation can becarried out in two parts by (i) adding an aldehyde or ketone to asolution of a compound of Formula XIVb or a salt thereof in a suitablesolvent such as DMF, THF, or methanol in the presence of a base such asN,N-diisopropylethylamine. In part (ii) the reduction is carried out byadding a suitable reducing agent such as the borane-pyridine complex.Both part (i) and part (ii) can be carried out at ambient temperature.

In some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme VIII wherein R_(A1), R_(B1), R₁, R₁′, R₂,and G are as defined above. The amino group of a compound of Formula IIcan be converted by conventional methods to a functional group such asan amide, carbamate, urea, amidine, or another hydrolyzable group. Acompound of this type can be made by the replacement of a hydrogen atomin an amino group with a group such as —C(O)—R′″, α-aminoacyl,α-aminoacyl-α-aminoacyl, —C(O)—O—R′″, —C(O)—N(R″″)R′″, —C(═NY₂)—R′″,—CH(OH)—C(O)—OY₂, —CH(OC₁₋₄ alkyl)Y₀, —CH₂Y₁, and —CH(CH₃)Y₁; whereinR′″ and R″″ are independently selected from the group consisting ofC₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, phenyl, benzyl, and 2-phenylethyl, each ofwhich may be unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of halogen, hydroxy,nitro, cyano, carboxy, C₁₋₆alkyl, C₁₋₄ alkoxy, aryl, heteroaryl,aryl-C₁₋₄ alkylenyl, heteroaryl-C₁₋₄ alkylenyl, halo-C₁₋₄ alkylenyl,halo-C₁₋₄ alkoxy, —O—C(O)—CH₃, —C(O)—O—CH₃, —C(O)—NH₂, —O—CH₂—C(O)—NH₂,—NH₂, and —(O)₂—NH₂, with the proviso that R″″ can also be hydrogen;each α-aminoacyl is an α-aminoacyl group derived from an α-amino acidselected from the group consisting of racemic, D-, and L-amino acids; Y₂is selected from the group consisting of hydrogen, C₁₋₆ alkyl, andbenzyl; Y₀ is selected from the group consisting of C₁₋₆ alkyl,carboxy-C₁₋₆ alkylenyl, amino-C₁₋₄ alkylenyl, mono-N—C₁₋₆alkylamino-C₁₋₄ alkylenyl, and di-N,N—C₁₋₆alkylamino-C₁₋₄ alkylenyl; andY₁ is selected from the group consisting of mono-N—C₁₋₆alkylamino,di-N,N—C₁₋₆ alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl,and 4-C₁₋₄ alkylpiperazin-1-yl. Particularly useful compounds of FormulaXV are amides derived from carboxylic acids containing one to ten carbonatoms, amides derived from amino acids, and carbamates containing one toten carbon atoms. The reaction can be carried out, for example, bycombining a compound of Formula II with a chloroformate or acidchloride, such as ethyl chloroformate or acetyl chloride, in thepresence of a base such as triethylamine in a suitable solvent such asdichloromethane at ambient temperature.

Pharmaceutical Compositions and Biological Activity

Pharmaceutical compositions of the invention contain a therapeuticallyeffective amount of a compound or salt described above in combinationwith a pharmaceutically acceptable carrier.

The terms “a therapeutically effective amount” and “effective amount”mean an amount of the compound or salt sufficient to induce atherapeutic or prophylactic effect, such as cytokine induction,immunomodulation, antitumor activity, and/or antiviral activity. Theexact amount of compound or salt used in a pharmaceutical composition ofthe invention will vary according to factors known to those of skill inthe art, such as the physical and chemical nature of the compound orsalt, the nature of the carrier, and the intended dosing regimen.

In some embodiments, the compositions of the invention will containsufficient active ingredient or prodrug to provide a dose of about 100nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram(mg/kg), preferably about 10 micrograms per kilogram (μg/kg) to about 5mg/kg, of the compound or salt to the subject.

In other embodiments, the compositions of the invention will containsufficient active ingredient or prodrug to provide a dose of, forexample, from about 0.01 mg/m² to about 5.0 mg/m², computed according tothe Dubois method, in which the body surface area of a subject (m²) iscomputed using the subject's body weight: m²=(wt kg^(0.425)×heightcm^(0.725))×0.007184, although in some embodiments the methods may beperformed by administering a compound or salt or composition in a doseoutside this range. In some of these embodiments, the method includesadministering sufficient compound to provide a dose of from about 0.1mg/m² to about 2.0 mg/m² to the subject, for example, a dose of fromabout 0.4 mg/m² to about 1.2 mg/m².

A variety of dosage forms may be used, such as tablets, lozenges,capsules, parenteral formulations, syrups, creams, ointments, aerosolformulations, transdermal patches, transmucosal patches and the like.These dosage forms can be prepared with conventional pharmaceuticallyacceptable carriers and additives using conventional methods, whichgenerally include the step of bringing the active ingredient intoassociation with the carrier.

The compounds or salts of the invention can be administered as thesingle therapeutic agent in the treatment regimen, or the compounds orsalts described herein may be administered in combination with oneanother or with other active agents, including additional immuneresponse modifiers, antivirals, antibiotics, antibodies, proteins,peptides, oligonucleotides, etc.

Compounds or salts of the invention have been shown to induce theproduction of certain cytokines in experiments performed according tothe tests set forth below. These results indicate that the compounds orsalts are useful for modulating the immune response in a number ofdifferent ways, rendering them useful in the treatment of a variety ofdisorders.

Cytokines whose production may be induced by the administration ofcompounds or salts of the invention generally include interferon-α(IFN-α) and tumor necrosis factor-α (TNF-α) as well as certaininterleukins (IL). Cytokines whose biosynthesis may be induced bycompounds or salts of the invention include IFN-α, TNF-α, IL-1, IL-6,IL-10 and IL-12, and a variety of other cytokines. Among other effects,these and other cytokines can inhibit virus production and tumor cellgrowth, making the compounds or salts useful in the treatment of viraldiseases and neoplastic diseases. Accordingly, the invention provides amethod of inducing cytokine biosynthesis in an animal comprisingadministering an effective amount of a compound or salt of the inventionto the animal. The animal to which the compound or salt is administeredfor induction of cytokine biosynthesis may have a disease as describedinfra, for example a viral disease or a neoplastic disease, andadministration of the compound or salt may provide therapeutictreatment. Alternatively, the compound or salt may be administered tothe animal prior to the animal acquiring the disease so thatadministration of the compound or salt may provide a prophylactictreatment.

In addition to the ability to induce the production of cytokines,compounds or salts described herein can affect other aspects of theinnate immune response. For example, natural killer cell activity may bestimulated, an effect that may be due to cytokine induction. Thecompounds or salts may also activate macrophages, which in turnstimulate secretion of nitric oxide and the production of additionalcytokines. Further, the compounds or salts may cause proliferation anddifferentiation of B-lymphocytes.

Compounds or salts described herein can also have an effect on theacquired immune response. For example, the production of the T helpertype 1 (T_(H)1) cytokine IFN-γ may be induced indirectly and theproduction of the T helper type 2 (T_(H)2) cytokines IL-4, IL-5 andIL-13 may be inhibited upon administration of the compounds or salts.

Whether for prophylaxis or therapeutic treatment of a disease, andwhether for effecting innate or acquired immunity, the compound or saltor composition may be administered alone or in combination with one ormore active components as in, for example, a vaccine adjuvant. Whenadministered with other components, the compound or salt or compositionand other component or components may be administered separately;together but independently such as in a solution; or together andassociated with one another such as (a) covalently linked or (b)non-covalently associated, e.g., in a colloidal suspension.

Conditions for which compounds or salts or compositions identifiedherein may be used as treatments include, but are not limited to:

(a) viral diseases such as, for example, diseases resulting frominfection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, orVZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, ormolluscum contagiosum), a picornavirus (e.g., rhinovirus orenterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus(e.g., parainfluenzavirus, mumps virus, measles virus, and respiratorysyncytial virus (RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g.,papillomaviruses, such as those that cause genital warts, common warts,or plantar warts), a hepadnavirus (e.g., hepatitis B virus), aflavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus(e.g., a lentivirus such as HIV);

(b) bacterial diseases such as, for example, diseases resulting frominfection by bacteria of, for example, the genus Escherichia,Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria,Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas,Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria,Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter,Vibrio, Serratia, Providencia, Chromobacterium, Brucella, Yersinia,Haemophilus, or Bordetella;

(c) other infectious diseases, such as chlamydia, fungal diseasesincluding but not limited to candidiasis, aspergillosis, histoplasmosis,cryptococcal meningitis, or parasitic diseases including but not limitedto malaria, pneumocystis carnii pneumonia, leishmaniasis,cryptosporidiosis, toxoplasmosis, and trypanosome infection;

(d) neoplastic diseases, such as intraepithelial neoplasias, cervicaldysplasia, actinic keratosis, basal cell carcinoma, squamous cellcarcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemiasincluding but not limited to acute myeloid leukemia, acute lymphocyticleukemia, chronic myeloid leukemia, chronic lymphocytic leukemia,multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneousT-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and othercancers;

(e) T_(H)2-mediated, atopic diseases, such as atopic dermatitis oreczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen'ssyndrome;

(f) certain autoimmune diseases such as systemic lupus erythematosus,essential thrombocythaemia, multiple sclerosis, discoid lupus, alopeciaareata; and

(g) diseases associated with wound repair such as, for example,inhibition of keloid formation and other types of scarring (e.g.,enhancing wound healing, including chronic wounds).

Additionally, a compound or salt identified herein may be useful as avaccine adjuvant for use in conjunction with any material that raiseseither humoral and/or cell mediated immune response, such as, forexample, live viral, bacterial, or parasitic immunogens; inactivatedviral, tumor-derived, protozoal, organism-derived, fungal, or bacterialimmunogens; toxoids; toxins; self-antigens; polysaccharides; proteins;glycoproteins; peptides; cellular vaccines; DNA vaccines; autologousvaccines; recombinant proteins; and the like, for use in connectionwith, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitisB, hepatitis C, influenza A, influenza B, parainfluenza, polio, rabies,measles, mumps, rubella, yellow fever, tetanus, diphtheria, hemophilusinfluenza b, tuberculosis, meningococcal and pneumococcal vaccines,adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline leukemia,fowl plague, HSV-1 and HSV-2, hog cholera, Japanese encephalitis,respiratory syncytial virus, rotavirus, papilloma virus, yellow fever,and Alzheimer's Disease.

Compounds or salts identified herein may be particularly helpful inindividuals having compromised immune function. For example, compoundsor salts may be used for treating the opportunistic infections andtumors that occur after suppression of cell mediated immunity in, forexample, transplant patients, cancer patients and HIV patients.

Thus, one or more of the above diseases or types of diseases, forexample, a viral disease or a neoplastic disease may be treated in ananimal in need thereof (having the disease) by administering atherapeutically effective amount of a compound or salt of the inventionto the animal.

An animal may also be vaccinated by administering an effective amount ofa compound or salt described herein, as a vaccine adjuvant. In oneembodiment, there is provided a method of vaccinating an animalcomprising administering an effective amount of a compound or saltdescribed herein to the animal as a vaccine adjuvant.

An amount of a compound or salt effective to induce cytokinebiosynthesis is an amount sufficient to cause one or more cell types,such as monocytes, macrophages, dendritic cells and B-cells to producean amount of one or more cytokines such as, for example, IFN-α, TNF-α,IL-1, IL-6, IL-10 and IL-12 that is increased (induced) over abackground level of such cytokines. The precise amount will varyaccording to factors known in the art but is expected to be a dose ofabout 100 ng/kg to about 50 mg/kg, preferably about 110 μg/kg to about 5mg/kg. In other embodiments, the amount is expected to be a dose of, forexample, from about 0.01 mg/m² to about 5.0 mg/m², (computed accordingto the Dubois method as described above) although in some embodimentsthe induction or inhibition of cytokine biosynthesis may be performed byadministering a compound or salt in a dose outside this range. In someof these embodiments, the method includes administering sufficientcompound or salt or composition to provide a dose of from about 0.1mg/m² to about 2.0 mg/m² to the subject, for example, a dose of fromabout 0.4 mg/m² to about 1.2 mg/m².

The invention also provides a method of treating a viral infection in ananimal and a method of treating a neoplastic disease in an animalcomprising administering an effective amount of a compound or salt ofthe invention to the animal. An amount effective to treat or inhibit aviral infection is an amount that will cause a reduction in one or moreof the manifestations of viral infection, such as viral lesions, viralload, rate of virus production, and mortality as compared to untreatedcontrol animals. The precise amount that is effective for such treatmentwill vary according to factors known in the art but is expected to be adose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg toabout 5 mg/kg. An amount of a compound or salt effective to treat aneoplastic condition is an amount that will cause a reduction in tumorsize or in the number of tumor foci. Again, the precise amount will varyaccording to factors known in the art but is expected to be a dose ofabout 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5mg/kg. In other embodiments, the amount is expected to be a dose of, forexample, from about 0.01 mg/m² to about 5.0 mg/m², (computed accordingto the Dubois method as described above) although in some embodimentseither of these methods may be performed by administering a compound orsalt in a dose outside this range. In some of these embodiments, themethod includes administering sufficient compound or salt to provide adose of from about 0.1 mg/m² to about 2.0 mg/m² to the subject, forexample, a dose of from about 0.4 mg/m² to about 1.2 mg/m².

In addition to the formulations and uses described specifically herein,other formulations, uses, and administration devices suitable forcompounds of the present invention are described in, for example,International Publication Nos. WO 03/077944 and WO 02/036592, U.S. Pat.No. 6,245,776, and U.S. Publication Nos. 2003/0139364, 2003/185835,2004/0258698, 2004/0265351, 2004/076633, and 2005/0009858.

Objects and advantages of this invention are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this invention.

EXAMPLES

In the examples below normal high performance flash chromatography (prepHPLC) was carried out using a HORIZON HPFC system (an automatedhigh-performance flash purification product available from Biotage, Inc,Charlottesville, Va., USA) or an INTELLIFLASH Flash ChromatographySystem (an automated flash purification system available from AnaLogix,Inc, Burlington, Wis., USA). The eluent used for each purification isgiven in the example. In some chromatographic separations, the solventmixture 80/18/2 v/v/v chloroform/methanol/concentrated ammoniumhydroxide (CMA) was used as the polar component of the eluent. In theseseparations, CMA was mixed with chloroform in the indicated ratio.

Example 1 2-Propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine

Part A

p-Toluenesulfonic acid (2 mg, 0.16 mmol) and acetonylacetone (2.14 g,18.7 mmol) were added sequentially to a solution of2-aminophenylacetonitrile (2.06 g, 15.6 mmol) in toluene (30 mL). Thereaction mixture was heated in an oil bath at 155° C. for 1 hour andthen allowed to stand at ambient temperature overnight. Acetonylacetone(0.5 mL) and a small amount of p-toluenesulfonic acid were added and thereaction mixture was heated at reflux for 4 hours. The toluene layer waswashed sequentially with saturated sodium bicarbonate and water (×2),dried over magnesium sulfate, filtered, and then concentrated underreduced pressure to a dark oil. The oil was purified by prep HPLC(AnaLogix, eluted with a gradient of 10-30% ethyl acetate in hexanes) toprovide 3.35 g of 2-(2,5-dimethylpyrrol-1-yl)phenylacetonitrile as apale brown oil.

Part B

2-(2,5-Dimethylpyrrol-1-yl)phenylacetonitrile (15 mmol) and diethyloxalate (4.38 g, 30 mml) were sequentially added neat washing withethanol (15 mL) to a solution of sodium tert-butoxide (1.73 g, 18 mmol)in ethanol (15 mL). The reaction mixture was heated at reflux under anitrogen atmosphere for 4.5 hours to provide a solution of ethyl3-cyano-3-[2-(2,5-dimethylpyrrol-1-yl)phenyl]-2-oxopropionate inethanol.

Part C

Acetic acid (12 mL) and n-propylhydrazine oxalate (985 mg g, 6.0 mmol)were added to a solution of ethyl3-cyano-3-[2-(2,5-dimethylpyrrol-1-yl)phenyl]-2-oxopropionate in ethanol(6.0 mmol in 12 mL). The reaction mixture was heated in an oil bath at100° C. for 1 hour and then concentrated under reduced pressure. Theresidue was diluted with 2 M sodium carbonate and then extracted withchloroform. The extract was dried over magnesium sulfate, filtered, andthen concentrated under reduced pressure to provide a black oil. The oilwas purified by prep HPLC (AnaLogix, eluted with a gradient of 2 to 50%CMA in chloroform) to provide a brown solid. This material was combinedwith chloroform and then tert-butyl methyl ether was added. A solid wasisolated by filtration, washed with tert-butyl methyl ether and dried toprovide 81 mg of1-amino-2-propyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a beigesolid, mp 266-268° C. MS (APCI) m/z 243 (M+H)⁺; Anal. Calcd forC₁₃H₁₄N₄O: C, 64.45; H, 5.82; N, 23.12. Found: C, 64.24; H, 5.86; N,23.05.

Acetic acid (30 mL) and n-propylhydrazine oxalate (9.85 g, 60 mmol) wereadded to the reaction mixture from Part B, which was then heated atreflux for 2.5 hours. The volatiles were removed under reduced pressure.The residue was made basic with 2 M sodium carbonate and then extractedwith chloroform. Water was added to break up the resulting emulsion. Theaqueous was back extracted with chloroform. The combined extracts weredried over magnesium sulfate, filtered, and then concentrated underreduced pressure to provide a black resin. Chloroform and hexanes wereadded sequentially to provide a brown solid. The solid was taken up in amixture of chloroform and methanol and then filtered to remove a smallamount of insoluble material. The filtrate provided 500 mg of material,which was absorbed onto silica gel (5 mL) and then purified by prep HPLC(Biotage, eluted with a gradient of 2-50% CMA in chloroform over 10column volumes) to provide 184 mg of1-amino-2-propyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a beigesolid. A portion of this material was used in Part D.

Part D

A solution of1-amino-2-propyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (86 mg,0.36 mmol) in phosphorus oxychloride (3 mL) was heated at 100° C. for 45minutes and then allowed to cool to ambient temperature. The reactionmixture was diluted with diethyl ether (10 mL). A solid was isolated byfiltration, rinsed with diethyl ether, and dried to provide4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-amine.

Part E

The material from Part D was combined with a solution of ammonia inmethanol (5 mL of 7 M) in a steel Parr vessel. The vessel was sealed andheated at 150° C. for 24 hours and then allowed to stand at ambienttemperature for 3 days. The reaction mixture was filtered to remove aprecipitate and the filter cake was washed with methanol. The filtratewas absorbed onto silica gel (3 mL) and purified by normal phase prepHPLC (AnaLogix, eluted with a gradient of 5-50% CMA in chloroform) toprovide 31 mg of a pale orange solid. This material was refluxed with75% ethyl acetate in hexanes, isolated by filtration, washed with 50%ethyl acetate in hexanes, and dried to provide about 25 mg of2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine, mp 253° C. (dec.).Anal. Calcd for: C₁₃H₁₅N₅.0.25H₂O: C, 63.52; H, 6.36; N, 28.50. Found:C, 63.58; H, 5.96; N, 28.50. Duplicate analysis Found: C, 63.30; H,6.10; N, 28.33.

Example 2 N¹-Ethyl-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine

Part A

2-Propyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one was prepared fromethyl 1H-indol-3-yl(oxo)acetate and propylhydrazine oxalate according tothe general procedure in the literature (Catarzi, D.; Colotta, V.;Varano, F.; Cecchi, L.; Filacchioni, G.; Galli, A.; Costagli, C. Arch.Pharm. Pharm. Med. Chem. 1997, 330, 383-386.).

Part B

A 12 L reaction vessel was charged with2-propyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (103.40 g, 455mmol), tetrahydrofuran (THF, 6.1 L), andN,N,N′,N′-tetramethylethylenediamine (392 mL, 2.59 mol), and theresulting suspension was cooled in an ice bath. n-Butyllithium (510 mLof a 2.5 M solution in hexane, 1.27 mol) was added over 65 minutes, andthe reaction was allowed to stir at 5° C. for 20 minutes. The contentsof the 12 L vessel were transferred via cannula over a period of 20minutes to a 22 L vessel containing dry ice (3 kg) and diethyl ether (2L). The reaction was stirred overnight, water (3 L) was added, theorganic layer was drawn off, and the aqueous layer was washed withchloroform (4×500 mL). The aqueous layer was acidified by treatment with2 M HCl (1.6 L), and the resulting suspension was stirred overnight. Thesolid was collected by filtration and dried on suction for 2 days toafford 69.47 g of4-oxo-2-propyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-1-carboxylic acidas an off-white solid.

Part C

4-Oxo-2-propyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-1-carboxylic acid(20 g, 73.7 mmol) was boiled in thionyl chloride (100 mL) and toluene(100 mL) for 7 hours. A small amount of insoluble powder was removed byfiltration, and the filtrate was concentrated, treated with toluene andconcentrated (2×), then dissolved in acetone (250 mL). The resultingsolution was cooled in an ice bath, and a solution of sodium azide (15.3g, 235 mmol) in water (40 mL) was added in one portion. The cooling bathwas removed, the reaction was stirred for 15 minutes more, and water(700 mL) was added to precipitate the product. The solid was collectedby filtration, washed with water, dried briefly on suction, andtransferred to a round-bottomed flask as a suspension in toluene. Thetoluene was removed at 30° C. under vacuum, and the solid wasconcentrated from toluene twice more. Toluene (200 mL) and tert-butanol(10 g, 135 mmol) were added, and the mixture was heated to reflux for 30minutes. Some insoluble material was removed by filtration, and thecontents of the filtrate were purified by prep HPLC (silica cartridge,eluting with 35% to 45% ethyl acetate in hexane). The resulting yellowfoam was recrystallized from 25% ethyl acetate in hexane (100 mL) toafford 16.29 g of tert-butyl4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-ylcarbamate as a paleyellow powder.

Part D

To a solution of tert-butyl4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-ylcarbamate (722 mg, 2.00mmol) in THF (5 mL) was added ethyl iodide (624 mg, 4.0 mmol). Sodiumhydride (120 mg of a 60 wt % dispersion in mineral oil, 3.00 mmol) wasadded, and after 40 min, more ethyl iodide (624 mg, 2.00 mmol) wasadded, and the reaction was stirred overnight. Saturated ammoniumchloride was added, and the aqueous layer was extracted with methyltert-butyl ether (3×). The combined organic layers were dried (magnesiumsulfate), filtered, concentrated, and purified by prep HPLC (silicacartridge, eluting with ethyl acetate in hexane) to afford 718 mg oftert-butyl4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl(ethyl)carbamate as awhite solid.

Part E

tert-Butyl4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl(ethyl)carbamate (718mg, 1.85 mmol) and methanolic ammonia (25 mL of a 7 M solution) wereheated in a steel Parr vessel in a 150° C. oven for 17 h. The reactionmixture was concentrated, treated with 2 M sodium carbonate andextracted with chloroform. The combined organic layers were dried(magnesium sulfate), filtered, concentrated, and purified by prep HPLC(silica cartridge, eluting with CMA in chloroform). The product wasrecrystallized from acetonitrile to afford 272 mg ofN¹-ethyl-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine as whitecrystals, mp 193-194° C. MS (APCI) m/z 270 (M+1)⁺; Anal. Calcd forC₁₅H₁₉N₅: C, 66.89; H, 7.11; N, 26.00. Found: C, 66.65; H, 7.20; N,26.19.

Example 3N¹-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine

Part A

tert-Butyl 4-(2-iodoethyl)piperidine-1-carboxylate (9.87 g, 29.1 mmol)was added to a solution of butyl4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-ylcarbamate (7.0 g, 19.4mmol) in THF (100 mL). Sodium hydride (60% in mineral oil, 1.16 g, 29.1mmol) was added and the reaction mixture was heated at reflux for 16hours. Saturated ammonium chloride (100 mL) was slowly added and thenthe mixture was extracted with methyl tert-butyl ether (2×100 mL). Thecombined organics were dried over sodium sulfate, filtered, and thenconcentrated under reduced pressure to provide a thick oil. The oil waspurified by prep HPLC (silica gel eluted with a linear gradient of 0 to15% CMA in chloroform, 2800 mL) to provide 9.52 g of tert-butyl4-{2-[(tert-butoxycarbonyl)(4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}piperidine-1-carboxylateas a white foam.

Part B

A solution of tert-butyl4-{2-[(tert-butoxycarbonyl)(4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}piperidine-1-carboxylate(1.41 g) in 7N ammonia in methanol (25 mL) was placed in a stainlesssteel pressure vessel and heated at 150° C. for 18 hours. The reactionmixture was cooled to ambient temperature and then concentrated underreduced pressure to provide a brown residue. The residue was suspendedin anhydrous ethanol (20 mL). Hydrochloric acid (4 mL of 3M) was addedand the reaction mixture was heated at reflux for 4 hours. The reactionmixture was concentrated under reduced pressure. The residue wastriturated with diethyl ether and the resulting solid was isolated byfiltration to provide 0.7 g ofN′-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diaminedihydrochloride as a brown solid. MS (APCI) m/z 353.30 (M+H)⁺. Theexperiment was repeated using 5.75 g of tert-butyl4-{2-[(tert-butoxycarbonyl)(4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}piperidine-1-carboxylatein 70 mL of 7N ammonia in methanol followed by treatment with 16.75 mLof 3M hydrochloric acid to provide 4.1 g of product as a brown solid. MS(APCI) m/z 353.26 (M+H)⁺.

Example 4N′-{2-[1-(Methylsulfonyl)piperidin-4-yl]ethyl}-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine

Methanesulfonyl chloride (0.30 g, 0.20 mL, 2.58 mmol) was added to astirring suspension ofN¹-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diaminedihydrochloride (1.0 g, 2.35 mmol) and triethylamine (0.59 g, 0.82 mL,5.88 mmol) in dichloromethane (10 mL). The resulting suspension wasstirred at ambient temperature 16 hours. Additional dichloromethane (90mL), triethylamine (4.2 g, 5.7 mL, 41.1 mmol) and methanesulfonylchloride (0.19 g, 0.13 mL, 1.66 mmol) were added to the mixture and theresulting cloudy suspension was stirred at ambient temperature 3 days.The reaction mixture was concentrated and the resulting brown solid waspurified by column chromatography using a HORIZON HPFC system (silicacartridge, eluting with 5-20% methanol in dichloromethane). Theresulting oil was crystallized from acetonitrile and isolated byfiltration to yield 169 mg ofN-{2-[1-(methylsulfonyl)piperidin-4-yl]ethyl}-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamineas an off-white solid, mp 204-207° C. Anal. calcd for C₂₁H₃₀N₆O₂S: C,58.58; H, 7.02; N, 19.52. Found: C, 58.77; H, 6.92; N, 19.54.

Example 54-{2-[(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}-N-isopropylpiperidine-1-carboxamide

Isopropyl isocyanate (0.29 g, 0.33 mL, 3.39 mmol) was added to astirring suspension ofN¹-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diaminedihydrochloride (1.2 g, 2.83 mmol) and triethylamine (2.9 g, 3.9 mL,28.3 mmol) in dichloromethane (100 mL). After 10 minutes,N,N-dimethylformamide (15 mL) was added and the resulting suspension wasstirred at ambient temperature 16 hours. The dichloromethane was removedunder reduced pressure and water (100 mL) was added to the resultingoil. A solid formed which was removed by filtration and discarded. Thefiltrate was transferred to a separatory funnel and extracted withdichloromethane (50 mL). The aqueous layer was saturated with solidsodium bicarbonate and extracted with dichlioromethane (3×50 mL). Theorganic fractions were combined, dried over magnesium sulfate, filtered,and concentrated under reduced pressure. The resulting brown oil waspurified by column chromatography using a HORIZON HPFC system (silicacartridge, eluting with 3-15% methanol in dichloromethane). Theresulting oil was crystallized from acetonitrile and isolated byfiltration to yield 132 mg of4-{2-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}-N-isopropylpiperidine-1-carboxamideas a white solid, mp 168-170° C. Anal. calcd for C₂₄H₃₅N₇O: C, 65.88; H,8.06; N, 22.41. Found: C, 65.89; H, 8.24; N, 22.67.

Example 6

N′-[2-(1-Acetylpiperidin-4-yl)ethyl]-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine

Acetyl chloride (0.27 g, 0.24 mL, 3.39 mmol) was added to a stirringsuspension ofN¹-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diaminedihydrochloride (1.2 g, 2.83 mmol) and triethylamine (2.9 g, 3.9 mL,28.3 mmol) in dichloromethane (100 mL). After 10 minutes,1-methyl-2-pyrrolidinone (15 mL) was added and the resulting suspensionwas stirred at ambient temperature 16 hours. Additional acetyl chloride(0.27 g, 0.24 mL, 3.39 mmol) was added and the suspension was stirred atambient temperature 4 hours. The dichloromethane was removed underreduced pressure and water (100 mL) was added to the resulting oil. Thesolution was transferred to a separatory funnel and extracted with ethylacetate (2×50 mL) and dichloromethane (50 mL). The organic layers werecombined, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. Methanol (20 mL) and sodium hydroxide (10 mL, 1 N inwater) were added to the resulting oil and the suspension was stirredone hour. The methanol was removed under reduced pressure and theaqueous layer was neutralized with hydrochloric acid (1 N in water) andextracted with dichloromethane (3×50 mL). The combined organic fractionswere dried over magnesium sulfate, filtered and concentrated underreduced pressure to 7.5 g of a yellow oil. Sodium carbonate (75 mL, 10%w/w in water) was added to this oil and a brown gum crashed out andstuck to the sides of the flask. The liquid was decanted off and theremaining gum was crystallized from hot acetonitrile (50 mL) andisolated by filtration to yield 242 mg ofN¹-[2-(1-acetylpiperidin-4-yl)ethyl]-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamineas a tan solid. mp 203-206° C. Anal. calcd for C₂₂H₃₀N₆O: C, 66.98; H,7.66; N, 21.30. Found: C, 66.92; H, 7.92; N, 21.57.

Examples 7-18

N¹-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diaminedihydrochloride (700 mg) was combined with N,N-diisopropylethylamine(1.4 mL) and sufficient N,N-dimethylacetamide to provide a total volumeof 16 mL. A portion (1.0 ml) was added to a tube containing a reagent(1.1 eq) from the table below. The reaction mixture was stirredovernight and then quenched with water (100 μL). The solvent was removedby vacuum centrifugation. The compounds were purified by preparativehigh performance liquid chromatography using a Waters FractionLynxautomated purification system. The fractions were analyzed using aWaters LC/TOF-MS, and the appropriate fractions were centrifugeevaporated to provide the trifluoroacetate salt of the desired compound.Reversed phase preparative liquid chromatography was performed withnon-linear gradient elution from 5-95% B where A is 0.05%trifluoroacetic acid/water and B is 0.05% trifluoroaceticacid/acetonitrile. Fractions were collected by mass-selectivetriggering. The table below shows the reagent used for each example, thestructure of the resulting compound, and the observed accurate mass forthe isolated trifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 7 Acetyl chloride

395.2530 8 Cyclopropanecarbonyl chloride

421.2685 9 Isobutyryl chloride

423.2836 10 Benzoyl chloride

457.2716 11 Methanesulfonyl chloride

431.2207 12 Isopropylsulfonyl chloride

459.2543 13 Dimethylsulfamoyl chloride

460.2489 14 Benzenesulfonyl chloride

493.2383 15 1-Methylimidazole- 4-sulfonyl chloride

497.2431 16 Methyl isocyanate

410.2664 17 Isopropyl isocyanate

438.2970 18 4- Morpholinylcarbonyl carbonyl

466.2916

Examples 19-32

The compounds in the table below were prepared and purified according tothe general method of Examples 7-18 except that the reaction mixtureswere stirred for 4 hours instead of overnight. The table below shows thereagent used for each example, the structure of the resulting compound,and the observed accurate mass for the isolated trifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 19 Propionyl chloride

409.2676 20 Methyl chloroformate

411.2481 21 Butyryl chloride

423.2859 22 Pivaloyl chloride

437.3002 23 Isovalery chloride

437.3009 24 Isoxazole-5- carbonyl chloride

448.2429 25 Ethanesulfonyl chloride

445.2346 26 1-Propanesulfonyl chloride

459.2499 27 1-Butanesulfonyl chloride

473.2683 28 Ethyl isocyanate

424.2790 29 N,N- Dimethylcarbamoyl carbonyl

424.2794 30 N-Propyl isocyanate

438.2968 31 1- Pyrrolidinecarbonyl chloride

450.2959 32 tert-Butyl isocyanate

452.3105

Examples 33 and 34

N¹-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diaminedihydrochloride (468 mg) was combined with N,N-diisopropylethylamine(383 μL) and sufficient methanol to provide a total volume of 11 mL. Aportion (1.0 ml) was added to a tube containing a reagent (1.25 eq) fromthe table below. The reaction mixture was stirred for 15 minutes.Borane-pyridine complex (16 μL) was added and the reaction mixture wasstirred for 4 hours. The solvent was removed by vacuum centrifugationand the compound was purified according to the method described inExamples 7-18. The table below shows the reagent used for each example,the structure of the resulting compound, and the observed accurate massfor the isolated trifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 33 2-Hydroxyacetaldehyde

397.2685 34 Benzaldehyde

443.2899

Example 35 N′-Methyl-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine

N′-Methyl-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine was preparedaccording to the general methods of Example 2 using methyl iodide inlieu of ethyl iodide in Part D. The product was provided as whitecrystals, mp 200-201° C. MS (APCI) m/z 256 (M+H)⁺; Anal. Calcd forC₁₄H₁₇N₅: C, 65.86; H, 6.71; N, 27.43. Found: C, 66.07; H, 6.50; N,27.81.

Example 36 N¹-Isopropyl-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine

N¹-Isopropyl-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine diaminewas prepared according to the general methods of Example 2 using2-iodopropane in lieu of ethyl iodide in Part D. The product wasprovided as a white solid, mp 199-200° C. MS (APCI) m/z 284 (M+H)⁺;Anal. Calcd for C₁₆H₂₁N₅: C, 67.82; H, 7.47; N, 24.71. Found: C, 67.60;H, 7.58; N, 24.77.

Example 37 N¹-Benzyl-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine

N¹-Benzyl-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine was preparedaccording to the general methods of Example 2 using benzyl bromide inlieu of ethyl iodide in Part D. The product was provided as a paleyellow solid, mp 160-161° C. MS (APCI) m/z 332 (M+H)⁺; Anal. Calcd forC₂₀H₂₁N₅: C, 72.48; H, 6.39; N, 21.13. Found: C, 72.71; H, 6.57; N,21.25.

Exemplary Compounds

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula IVj and the following R₁ and R₂substituents, wherein each line of the table is matched with Formula IVjto represent a specific embodiment of the invention.

IVj

R₁ R₂ methyl methyl methyl ethyl methyl n-propyl methyl n-butyl methyl2-methoxyethyl methyl 2-hydroxyethyl ethyl methyl ethyl ethyl ethyln-propyl ethyl n-butyl ethyl 2-methoxyethyl ethyl 2-hydroxyethyln-propyl methyl n-propyl ethyl n-propyl n-propyl n-propyl n-butyln-propyl 2-methoxyethyl n-propyl 2-hydroxyethyl 1-methylethyl methyl1-methylethyl ethyl 1-methylethyl n-propyl 1-methylethyl n-butyl1-methylethyl 2-methoxyethyl 1-methylethyl 2-hydroxyethyl n-butyl methyln-butyl ethyl n-butyl n-propyl n-butyl n-butyl n-butyl 2-methoxyethyln-butyl 2-hydroxyethyl 1-ethylpropyl methyl 1-ethylpropyl ethyl1-ethylpropyl n-propyl 1-ethylpropyl n-butyl 1-ethylpropyl2-methoxyethyl 1-ethylpropyl 2-hydroxyethyl 2-methylpropyl methyl2-methylpropyl ethyl 2-methylpropyl n-propyl 2-methylpropyl n-butyl2-methylpropyl 2-methoxyethyl 2-methylpropyl 2-hydroxyethyl3-methylbutyl methyl 3-methylbutyl ethyl 3-methylbutyl n-propyl3-methylbutyl n-butyl 3-methylbutyl 2-methoxyethyl 3-methylbutyl2-hydroxyethyl benzyl methyl benzyl ethyl benzyl n-propyl benzyl n-butylbenzyl 2-methoxyethyl benzyl 2-hydroxyethyl 2-phenylethyl methyl2-phenylethyl ethyl 2-phenylethyl n-propyl 2-phenylethyl n-butyl2-phenylethyl 2-methoxyethyl 2-phenylethyl 2-hydroxyethyl 3-phenylpropylmethyl 3-phenylpropyl ethyl 3-phenylpropyl n-propyl 3-phenylpropyln-butyl 3-phenylpropyl 2-methoxyethyl 3-phenylpropyl 2-hydroxyethyl

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula XIVe and the following R₂, X₁,and —Y—R₄ substituents, wherein each line of the table is matched withFormula XIVe to represent a specific embodiment of the invention.

XIVe

X₁ —Y—R₄ R₂ —CH₂— —C(O)—CH₃ methyl —CH₂— —C(O)—CH₃ ethyl —CH₂— —C(O)—CH₃n-propyl —CH₂— —C(O)—CH₃ n-butyl —CH₂— —C(O)—CH₃ 2-methoxyethyl —CH₂——C(O)—CH₃ 2-hydroxyethyl —CH₂— —S(O)₂—CH₃ methyl —CH₂— —S(O)₂—CH₃ ethyl—CH₂— —S(O)₂—CH₃ n-propyl —CH₂— —S(O)₂—CH₃ n-butyl —CH₂— —S(O)₂—CH₃2-methoxyethyl —CH₂— —S(O)₂—CH₃ 2-hydroxyethyl —CH₂— —C(O)—NH—CH(CH₃)₂methyl —CH₂— —C(O)—NH—CH(CH₃)₂ ethyl —CH₂— —C(O)—NH—CH(CH₃)₂ n-propyl—CH₂— —C(O)—NH—CH(CH₃)₂ n-butyl —CH₂— —C(O)—NH—CH(CH₃)₂ 2-methoxyethyl—CH₂— —C(O)—NH—CH(CH₃)₂ 2-hydroxyethyl —CH₂CH₂— —C(O)—CH₃ methyl—CH₂CH₂— —C(O)—CH₃ ethyl —CH₂CH₂— —C(O)—CH₃ n-propyl —CH₂CH₂— —C(O)—CH₃n-butyl —CH₂CH₂— —C(O)—CH₃ 2-methoxyethyl —CH₂CH₂— —C(O)—CH₃2-hydroxyethyl —CH₂CH₂— —S(O)₂—CH₃ methyl —CH₂CH₂— —S(O)₂—CH₃ ethyl—CH₂CH₂— —S(O)₂—CH₃ n-propyl —CH₂CH₂— —S(O)₂—CH₃ n-butyl —CH₂CH₂——S(O)₂—CH₃ 2-methoxyethyl —CH₂CH₂— —S(O)₂—CH₃ 2-hydroxyethyl —CH₂CH₂——C(O)—NH—CH(CH₃)₂ methyl —CH₂CH₂— —C(O)—NH—CH(CH₃)₂ ethyl —CH₂CH₂——C(O)—NH—CH(CH₃)₂ n-propyl —CH₂CH₂— —C(O)—NH—CH(CH₃)₂ n-butyl —CH₂CH₂——C(O)—NH—CH(CH₃)₂ 2-methoxyethyl —CH₂CH₂— —C(O)—NH—CH(CH₃)₂2-hydroxyethyl

Compounds of the invention have been found to modulate cytokinebiosynthesis by inducing the production of interferon α and/or tumornecrosis factor α in human cells when tested using one of the methodsdescribed below.

Cytokine Induction in Human Cells

An in vitro human blood cell system is used to assess cytokineinduction. Activity is based on the measurement of interferon (α) andtumor necrosis factor (α) (IFN-α and TNF-α, respectively) secreted intoculture media as described by Testerman et. al. in “Cytokine Inductionby the Immunomodulators Imiquimod and S-27609”, Journal of LeukocyteBiology, 58, 365-372 (September, 1995).

Blood Cell Preparation for Culture

Whole blood from healthy human donors is collected by venipuncture intovacutainer tubes or syringes containing EDTA. Peripheral bloodmononuclear cells (PBMC) are separated from whole blood by densitygradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, Mo.) orFicoll-Paque Plus (Axnersham Biosciences Piscataway, N.J.). Blood isdiluted 1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank'sBalanced Salts Solution (HBSS). Alternately, whole blood is placed inAccuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, Fla.)centrifuge frit tubes containing density gradient medium. The PBMC layeris collected and washed twice with DPBS or HBSS and re-suspended at4×10⁶ cells/mL in RPMI complete. The PBMC suspension is added to 96 wellflat bottom sterile tissue culture plates containing an equal volume ofRPMI complete media containing test compound.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. The compounds are generally tested atconcentrations ranging from 30-0.014 μM. Controls include cell sampleswith media only, cell samples with DMSO only (no compound), and cellsamples with reference compound.

Incubation

The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial 3 fold dilutions are made in thewells. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range(usually 30-0.014 μM). The final concentration of PBMC suspension is2×10⁶ cells/mL. The plates are covered with sterile plastic lids, mixedgently and then incubated for 18 to 24 hours at 37° C. in a 5% carbondioxide atmosphere.

Separation

Following incubation the plates are centrifuged for 10 minutes at 1000rpm (approximately 200×g) at 4° C. The cell-free culture supernatant isremoved and transferred to sterile polypropylene tubes. Samples aremaintained at −30 to −70° C. until analysis. The samples are analyzedfor IFN-α by ELISA and for TNF-α by IGEN/Bio Veris Assay.

Interferon (α) and Tumor Necrosis Factor (α) Analysis

IFN-α concentration is determined with a human multi-subtypecalorimetric sandwich ELISA (Catalog Number 41105) from PBL BiomedicalLaboratories, Piscataway, N.J. Results are expressed in pg/mL.

The TNF-α concentration is determined by ORIGEN M-Series Immunoassay andread on an IGEN M-8 analyzer from BioVeris Corporation, formerly knownas IGEN International, Gaithersburg, Md. The immunoassay uses a humanTNF-α capture and detection antibody pair (Catalog Numbers AHC3419 andAHC3712) from Biosource International, Camarillo, Calif. Results areexpressed in pg/mL.

Assay Data and Analysis

In total, the data output of the assay consists of concentration valuesof TNF-α and IFN-α (y-axis) as a function of compound concentration(x-axis).

Analysis of the data has two steps. First, the greater of the mean DMSO(DMSO control wells) or the experimental background (usually 20 pg/mLfor IFN-α and 40 pg/mL for TNF-α) is subtracted from each reading. Ifany negative values result from background subtraction, the reading isreported as “*”, and is noted as not reliably detectable. In subsequentcalculations and statistics, “*”, is treated as a zero. Second, allbackground subtracted values are multiplied by a single adjustment ratioto decrease experiment to experiment variability. The adjustment ratiois the area of the reference compound in the new experiment divided bythe expected area of the reference compound based on the past 61experiments (unadjusted readings). This results in the scaling of thereading (y-axis) for the new data without changing the shape of thedose-response curve. The reference compound used is2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91) and the expected area isthe sum of the median dose values from the past 61 experiments.

The minimum effective concentration is calculated based on thebackground-subtracted, reference-adjusted results for a given experimentand compound. The minimum effective concentration (μmolar) is the lowestof the tested compound concentrations that induces a response over afixed cytokine concentration for the tested cytokine (usually 20 pg/mLfor IFN-α and 40 pg/mL for TNF-α). The maximal response is the maximalamount of cytokine (pg/ml) produced in the dose-response.

Cytokine Induction in Human Cells High Throughput Screen

The CYTOKINE INDUCTION IN HUMAN CELLS test method described above wasmodified as follows for high throughput screening.

Blood Cell Preparation for Culture

Whole blood from healthy human donors is collected by venipuncture intovacutainer tubes or syringes containing EDTA. Peripheral bloodmononuclear cells (PBMC) are separated from whole blood by densitygradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, Mo.) orFicoll-Paque Plus (Amersham Biosciences Piscataway, N.J.). Whole bloodis placed in Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc.,Longwood, Fla.) centrifuge frit tubes containing density gradientmedium. The PBMC layer is collected and washed twice with DPBS or HBSSand re-suspended at 4×10⁶ cells/mL in RPMI complete (2-fold the finalcell density). The PBMC suspension is added to 96-well flat bottomsterile tissue culture plates.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). Thecompounds are generally tested at concentrations ranging from 30-0.014μM. Controls include cell samples with media only, cell samples withDMSO only (no compound), and cell samples with a reference compound2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91) on each plate. Thesolution of test compound is added at 7.5 mM to the first well of adosing plate and serial 3 fold dilutions are made for the 7 subsequentconcentrations in DMSO. RPMI Complete media is then added to the testcompound dilutions in order to reach a final compound concentration of2-fold higher (60-0.028 μM) than the final tested concentration range.

Incubation

Compound solution is then added to the wells containing the PBMCsuspension bringing the test compound concentrations to the desiredrange (usually 30-0.014 μM) and the DMSO concentration to 0.4%. Thefinal concentration of PBMC suspension is 2×10⁶ cells/mL. The plates arecovered with sterile plastic lids, mixed gently and then incubated for18 to 24 hours at 37° C. in a 5% carbon dioxide atmosphere.

Separation

Following incubation the plates are centrifuged for 10 minutes at 1000rpm (approximately 200 g) at 4° C. 4-plex Human Panel MSD MULTI-SPOT96-well plates are pre-coated with the appropriate capture antibodies byMesoScale Discovery, Inc. (MSD, Gaithersburg, Md.). The cell-freeculture supernatants are removed and transferred to the MSD plates.Fresh samples are typically tested, although they may be maintained at−30 to −70° C. until analysis.

Interferon-α and Tumor Necrosis Factor-α Analysis

MSD MULTI-SPOT plates contain within each well capture antibodies forhuman TNF-α and human IFN-α that have been pre-coated on specific spots.Each well contains four spots: one human TNF-α capture antibody (MSD)spot, one human IFN-α capture antibody (PBL Biomedical Laboratories,Piscataway, N.J.) spot, and two inactive bovine serum albumin spots. Thehuman TNF-α capture and detection antibody pair is from MesoScaleDiscovery. The human IFN-α multi-subtype antibody (PBL BiomedicalLaboratories) captures all IFN-α subtypes except IFN-α F (IFNα21).Standards consist of recombinant human TNF-α (R&D Systems, Minneapolis,Minn.) and IFN-α (PBL Biomedical Laboratories). Samples and separatestandards are added at the time of analysis to each MSD plate. Two humanIFN-α detection antibodies (Cat. Nos. 21112 & 21100, PBL) are used in atwo to one ratio (weight:weight) to each other to determine the IFN-αconcentrations. The cytokine-specific detection antibodies are labeledwith the SULFO-TAG reagent (MSD). After adding the SULFO-TAG labeleddetection antibodies to the wells, each well's electrochemoluminescentlevels are read using MSD's SECTOR HTS READER. Results are expressed inpg/mL upon calculation with known cytokine standards.

Assay Data and Analysis

In total, the data output of the assay consists of concentration valuesof TNF-α or IFN-α (y-axis) as a function of compound concentration(x-axis).

A plate-wise scaling is performed within a given experiment aimed atreducing plate-to-plate variability associated within the sameexperiment. First, the greater of the median DMSO (DMSO control wells)or the experimental background (usually 20 pg/mL for IFN-α and 40 pg/mLfor TNF-α) is subtracted from each reading. Negative values that mayresult from background subtraction are set to zero. Each plate within agiven experiment has a reference compound that serves as a control. Thiscontrol is used to calculate a median expected area under the curveacross all plates in the assay. A plate-wise scaling factor iscalculated for each plate as a ratio of the area of the referencecompound on the particular plate to the median expected area for theentire experiment. The data from each plate are then multiplied by theplate-wise scaling factor for all plates. Only data from plates bearinga scaling factor of between 0.5 and 2.0 (for both cytokines IFN-α,TNF-α) are reported. Data from plates with scaling factors outside theabove mentioned interval are retested until they bear scaling factorsinside the above mentioned interval. The above method produces a scalingof the y-values without altering the shape of the curve. The referencecompound used is2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91). The median expected areais the median area across all plates that are part of a givenexperiment.

A second scaling may also be performed to reduce inter-experimentvariability (across multiple experiments). All background-subtractedvalues are multiplied by a single adjustment ratio to decreaseexperiment-to-experiment variability. The adjustment ratio is the areaof the reference compound in the new experiment divided by the expectedarea of the reference compound based on an average of previousexperiments (unadjusted readings). This results in the scaling of thereading (y-axis) for the new data without changing the shape of thedose-response curve. The reference compound used is2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91) and the expected area isthe sum of the median dose values from an average of previousexperiments.

The minimum effective concentration is calculated based on thebackground-subtracted, reference-adjusted results for a given experimentand compound. The minimum effective concentration (μmolar) is the lowestof the tested compound concentrations that induces a response over afixed cytokine concentration for the tested cytokine (usually 20 pg/mLfor IFN-α and 40 pg/mL for TNF-α). The maximal response is the maximalamount of cytokine (pg/ml) produced in the dose-response.

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. Variousmodifications and alterations to this invention will become apparent tothose skilled in the art without departing from the scope and spirit ofthis invention. It should be understood that this invention is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein and that such examples and embodiments arepresented by way of example only with the scope of the inventionintended to be limited only by the claims set forth herein as follows.

1. A compound of the Formula I:

wherein: R₁ is selected from the group consisting of: —R₄, —Y—R₄,—X—N(R₈)—Y—R₄, —X—C(R₆)—N(R₈)—R₄, —X—O—C(R₆)—N(R₈)—R₄,—X—S(O)₂—N(R₈)—R₄, —X—O—R₄, and —X—R₅; R₁′ is selected from the groupconsisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenylwherein the alkylenyl group contains at least two carbon atoms betweenthe hydroxy or alkoxy substituent and the nitrogen atom to which R₁′ isbonded; or R₁ and R₁′ together with the nitrogen atom to which they arebonded can join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—; X is C_(2-2O) alkylene; Y is selectedfrom the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—, —S(O)₂—N(R₈)—,and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from the group consisting ofhydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄ together with thenitrogen atom to which R₁₁ is bonded can join to form the group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4; R_(A) and R_(B) are eachindependently selected from the group consisting of: hydrogen, halogen,alkyl, alkenyl, alkoxy, alkylthio, and —N(R₉)₂; or when taken together,R_(A) and R_(B) form a fused aryl ring or heteroaryl ring containing oneheteroatom selected from the group consisting of N and S, wherein thearyl or heteroaryl ring is unsubstituted or substituted by one or moreR′ groups; or when taken together, R_(A) and R_(B) form a fused 5 to 7membered saturated ring, optionally containing one heteroatom selectedfrom the group consisting of N and S, and unsubstituted or substitutedby one or more R groups; R is selected from the group consisting of:halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and—N(R₉)₂; R₄ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl,haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl,aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy,heterocyclyl, heterocyclylalkylenyl, amino, alkylamino,(arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl,alkynyl, and heterocyclyl, oxo, with the proviso that when R₁ is R₄, R₄is a substituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁ is bonded; R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R′ is a non-interfering substituent; and R″ ishydrogen or a non-interfering substituent; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1 wherein Formula I isFormula II:

wherein: R₁ is selected from the group consisting of: —R₄, —Y—R₄,—X—N(R₈)—Y—R₄, —X—C(R₆)—N(R₈)—R₄, —X—O—C(R₆)—N(R₈)—R₄,—X—S(O)₂—N(R₈)—R₄, —X—O—R₄, and —X—R₅; R₁′ is selected from the groupconsisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenylwherein the alkylenyl group contains at least two carbon atoms betweenthe hydroxy or alkoxy substituent and the nitrogen atom to which R₁′ isbonded; or R₁ and R₁′ together with the nitrogen atom to which they arebonded can join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—; X is C₂₋₂₀ alkylene; Y is selectedfrom the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—, —S(O)₂—N(R₈)—,and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from the group consisting ofhydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄ together with thenitrogen atom to which R₁₁ is bonded can join to form the group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4; R_(A1) and R_(B1) are eachindependently selected from the group consisting of: hydrogen, halogen,alkyl, alkenyl, alkoxy, alkylthio, and —N(R₉)₂; or when taken together,R_(A1) and R_(B1) form a fused aryl ring or heteroaryl ring containingone heteroatom selected from the group consisting of N and S, whereinthe aryl or heteroaryl ring is unsubstituted or substituted by one ormore R groups, or substituted by one R₃ group, or substituted by one R₃group and one R group; or when taken together, R_(A1) and R_(B1) form afused 5 to 7 membered saturated ring, optionally containing oneheteroatom selected from the group consisting of N and S, andunsubstituted or substituted by one or more R groups; R is selected fromthe group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl,alkoxy, alkylthio, and —N(R₉)₂; R₂ is selected from the group consistingof: —R₄′, —X′—R₄′ —X′—Y′—R₄′, and —X′—R₅′; R₃ is selected from the groupconsisting of: -Z-R₄′, -Z-X′—R₄′, -Z-X′—Y′—R₄′, -Z-X′—Y′—X′—Y′—R₄′, and-Z-X′—R₅′; R₄ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl,haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl,aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy,heterocyclyl, heterocyclylalkylenyl, amino, alkylamino,(arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl,alkynyl, and heterocyclyl, oxo, with the proviso that when R₁ is R₄, R₄is a substituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R, is bonded; R₄′ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A′ is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A″ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; X′ is selected from the groupconsisting of alkylene, alkenylene, alkenylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated by arylene,heteroarylene or heterocyclylene and optionally interrupted by one ormore —O— groups; Y′ is selected from the group consisting of:

Z is a bond or —O—; and c and d are independently integers from 1 to 6with the proviso that c+d is ≦7; or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 1 wherein Formula I is Formula III:

wherein: R₁ is selected from the group consisting of: —R₄, —Y—R₄,—X—N(R₈)—Y—R₄, —X—C(R₆)—N(R₈)—R₄, —X—O—C(R₆)—N(R₈)—R₄,—X—S(O)₂—N(R₈)—R₄, —X—O—R₄, and —X—R₅; R₁′ is selected from the groupconsisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenylwherein the alkylenyl group contains at least two carbon atoms betweenthe hydroxy or alkoxy substituent and the nitrogen atom to which R₁′ isbonded; or R₁ and R₁′ together with the nitrogen atom to which they arebonded can join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—; X is C₂₋₂₀ alkylene; Y is selected fromthe group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—, —S(O)₂—N(R₈)—, and—C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from the group consisting ofhydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄ together with thenitrogen atom to which R₁₁ is bonded can join to form the group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4; R_(A2) and R_(B2) are eachindependently selected from the group consisting of: hydrogen, halogen,alkyl, alkenyl, alkoxy, alkylthio, and —N(R₉)₂; R₂ is selected from thegroup consisting of: —X′——Y′—R₄′, and —X₁—R₅′ R₄ is selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,and heterocyclyl groups can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto,cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl,heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl,amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the caseof alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso thatwhen R₁ is R₄, R₄ is a substituted alkyl group, and the substituentcontains a hetero atom which bonds directly to the alkyl group, then thealkyl group contains at least two carbons between the substituent andthe nitrogen atom to which R₁ is bonded; R₄′ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A′ is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A″ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group. consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; X′ is selected from the groupconsisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated by arylene,heteroarylene or heterocyclylene and optionally interrupted by one ormore —O— groups; Y′ is selected from the group consisting of:

c and d are independently integers from 1 to 6 with the proviso that c+dis ≦7; or a pharmaceutically acceptable salt thereof.
 4. The compound ofclaim 1 wherein Formula I is IV:

wherein: R₁ is selected from the group consisting of: —R₄, —Y—R₄,—X—N(R₈)—Y—R₄, —X—C(R₆)—N(R₈)—R₄, —X—O—C(R₆)—N(R₈)—R₄,—X—S(O)₂—N(R₈)—R₄, —X—O—R₄, and —X—R₅; R₁′ is selected from the groupconsisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenylwherein the alkylenyl group contains at least two carbon atoms betweenthe hydroxy or alkoxy substituent and the nitrogen atom to which R₁′ isbonded; or R₁ and R₁′ together with the nitrogen atom to which they arebonded can join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₅)—Y—R₄)—; X is C₂₋₂₀ alkylene; Y is selectedfrom the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—, —S(O)₂N(R₈)—,and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from the group consisting ofhydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄ together with thenitrogen atom to which R₁₁ is bonded can join to form the group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4; R is selected from the groupconsisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy,alkylthio, and N(R₉)₂; n is an integer from 0 to 4; R₂ is selected fromthe group consisting of: —R₄′, —X′—R₄′, —X′—Y′—R₄′, and —X′—R₅′; R₃ isselected from the group consisting of: -Z-R₄′, -Z-X′—R₄′, -Z-X′—Y′—R₄′,-Z-X′—Y′—X′—Y′—R₄′, and -Z-X′—R₅′; m is 0 or 1 with the proviso thatwhen m is 1 then n is 0 or 1; R₄ is selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclylwherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclylgroups can be unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, alkoxy,haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano,carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy,heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino,alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case ofalkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso thatwhen R₁, is R₄, R₄ is a substituted alkyl group, and the substituentcontains a hetero atom which bonds directly to the alkyl group, then thealkyl group contains at least two carbons between the substituent andthe nitrogen atom to which R₁ is bonded; R₄′ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A′ is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A″ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; X′ is selected from the groupconsisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkenylenegroups can be optionally interrupted or terminated by arylene,heteroarylene or heterocyclylene and optionally interrupted by one ormore —O— groups; Y is selected from the group consisting of:

Z is a bond or —O—; and c and d are independently integers from 1 to 6with the proviso that c+d is ≦7; or a pharmaceutically acceptable saltthereof.
 5. The compound of claim 1 wherein Formula I is V:

wherein: R₁ is selected from the group consisting of: —R₄, —Y—R₄,—X—N(R₈)—Y—R₄, —X—C(R₆)—N(R₈)—R₄, —X—O—C(R₆)—N(R₈)—R₄,—X—S(O)₂—N(R₈)—R₄, —X—O—R₄, and —X—R₅; R₁′ is selected from the groupconsisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenylwherein the alkylenyl group contains at least two carbon atoms betweenthe hydroxy or alkoxy substituent and the nitrogen atom to which R₁′ isbonded; or R₁ and R₁′ together with the nitrogen atom to which they arebonded can join to form a group selected from the group consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—; X is C₂₋₂₀ alkylene; Y is selectedfrom the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—, —S(O)₂—N(R₈)—,and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from the group consisting ofhydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄ together with thenitrogen atom to which R₁₁ is bonded can join to form the group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, —N(R₈)—, —N(Y—R₄)—, or —N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4; R is selected from the groupconsisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy,alkylthio, and N(R₉)₂; n is an integer from 0 to 4; R₂ is selected fromthe group consisting of: —X′—Y′—R₄′, and —X′—R₅′; R₄ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl groups can be unsubstituted or substitutedby one or more substituents independently selected from the groupconsisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro,hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy,heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,dialkylamino, and in the case of alkyl, alkenyl, alkynyl, andheterocyclyl, oxo, with the proviso that when R₁ is R₄, R₄ is asubstituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁ is bonded; R₄′ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalltyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A′ is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A″ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄) and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉) V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; X′ is selected from the groupconsisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated by arylene,heteroarylene or heterocyclylene and optionally interrupted by one ormore —O— groups; Y′ is selected from the group consisting of:

c and d are independently integers from 1 to 6 with the proviso that c+dis ≦7; or a pharmaceutically acceptable salt thereof.
 6. The compound ofclaim 1 wherein Formula I is XIV:

wherein: X₁ is a bond or C₁₋₄ alkylene; A₁ is selected from the groupconsisting of —N(R₈)— and —N(—Y—R₄)—; Y is selected from the groupconsisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—, —S(O)₂—N(R₈)—, and—C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from the group consisting ofhydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄ together with thenitrogen atom to which R₁₁ is bonded can join to form the group

A is selected from the group consisting of —CH(R₈)—, —O—, N(R₈)—,—N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—; a and b are independently integersfrom 1 to 4 with the proviso that when A is —O—, —N(R₈)—, —N(Y—R₄)—, or—N(X—N(R₈)—Y—R₄)— then a and b are independently integers from 2 to 4; Xis C₂₋₂₀ alkylene; R₁′ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl wherein thealkylenyl group contains at least two carbon atoms between the hydroxyor alkoxy substituent and the nitrogen atom to which R₁′ is bonded;R_(A1) and R_(B1) are each independently selected from the groupconsisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and—N(R₉)₂; or when taken together, R_(A1) and R_(B1) form a fused arylring or heteroaryl ring containing one heteroatom selected from thegroup consisting of N and S, wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R groups, or substituted byone R₃ group, or substituted by one R₃ group and one R group; or whentaken together, R_(A1) and R_(B1) form a fused 5 to 7 membered saturatedring, optionally containing one heteroatom selected from the groupconsisting of N and S, and unsubstituted or substituted by one or more Rgroups; R is selected from the group consisting of: halogen, hydroxy,alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and —N(R₉)₂; R₂ isselected from the group consisting of: —R₄′, —X′—R₄′ —X′—Y′—R₄′, and—X′—R₅′; R₃ is selected from the group consisting of: -Z-R₄′, -Z-X′—R₄′,-Z-X′—Y′-R₄′, -Z-X′—Y′—X′—Y′—R₄′, and -Z-X′—R₅′; R₄ is selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,and heterocyclyl groups can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto,cyan, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl,heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl,amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the caseof alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso thatwhen R₁ is R₄, R₄ is a substituted alkyl group, and the substituentcontains a hetero atom which bonds directly to the alkyl group, then thealkyl group contains at least two carbons between the substituent andthe nitrogen atom to which R₁ is bonded; R₄′ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, allylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A′ is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A″ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; X′ is selected from the groupconsisting of alkylene, alkenylene, alkenylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated by arylene,heteroarylene or heterocyclylene and optionally interrupted by one ormore —O— groups; Y′ is selected from the group consisting of:

Z is a bond or —O—; and c and d are independently integers from 1 to 6with the proviso that c+d is ≦7; or a pharmaceutically acceptable saltthereof.
 7. A compound of the Formula XV:

wherein: G is selected from the group consisting of: —C(O)—R′″,α-aminoacyl, α-aminoacyl-α-aminoacyl, —C(O)—O—R′″, —C(O)—N(R″″)R′″—C(═NY₂)—R′″, —CH(OH)—C(O)—OY₂, —CH(OC₁₋₄alkyl)Y₀, —CH₂Y₁, and—CH(CH₃)Y₁; R′″ and R″″ are independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, phenyl, benzyl, and2-phenylethyl, each of which may be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofhalogen, hydroxy, nitro, cyano, carboxy, C₁₋₆alkyl, C₁₋₄alkoxy, aryl,heteroaryl, aryl-C₁₋₄alkylenyl, heteroaryl-C₁₋₄alkylenyl,halo-C₁₋₄alkylenyl, halo-C₁₋₄alkoxy, —O—C(O)—CH₃, —C(O)—O—CH₃,—C(O)—NH₂, —O—CH₂—C(O)—NH₂, —NH₂, and —S(O)₂—NH₂, with the proviso thatR″″ can also be hydrogen; α-aminoacyl is an α-aminoacyl group derivedfrom an α-amino acid selected from the group consisting of racemic, D-,and L-amino acids; Y₂ is selected from the group consisting of hydrogen,C₁₋₆ alkyl, and benzyl; Y₀ is selected from the group consisting of C₁₋₆alkyl, carboxy-C₁₋₆ alkylenyl, amino-C₁₋₄ alkylenyl, mono-N—C₁₋₆alkylamino-C₁₋₄ alkylenyl, and di-N,N—C₁₋₆ alkylamino-C₁₋₄ alkylenyl; Y₁is selected from the group consisting of mono-N—C₁₋₆ alkylamino,di-N,N—C₁₋₆ alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl,and 4-C₁₋₁₄ alkylpiperazin-1-yl; R₁ is selected from the groupconsisting of: —R₄, Y—R₄, —X—N(R₈)—Y—R₄, —X—C(R₆)—N(R₈)—R₄,—X—O—C(R₆)—N(R₈)—R₄, —X—S(O)₂—N(R₈)—R₄, —X—O—R₄, and —X—R₅; R₁′ isselected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl,and hydroxyalkylenyl wherein the alkylenyl group contains at least twocarbon atoms between the hydroxy or alkoxy substituent and the nitrogenatom to which R₁′ is bonded; or R₁ and R₁′ together with the nitrogenatom to which they are bonded can join to form a group selected from thegroup consisting of:

A is selected from the group consisting of —CH(R₈)—, —O—, N(R₈)—,N(Y—R₄)—, and N(X—N(R₈)—Y—R₄)—; X is C₂₋₂₀ alkylene; Y is selected fromthe group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—, —S(O)₂—N(R₈)—, and—C(R₆)—N(R₁₁)—; wherein R₁, is selected from the group consisting ofhydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄ together with thenitrogen atom to which R₁₁ is bonded can join to form the group

a and b are independently integers from 1 to 4 with the proviso thatwhen A is —O—, N(R₈)—, —N(Y—R₄)—, or N(X—N(R₈)—Y—R₄)— then a and b areindependently integers from 2 to 4; R_(A1) and R_(B1) are eachindependently selected from the group consisting of: hydrogen, halogen,alkyl, alkenyl, alkoxy, alkylthio, and N(R₉)₂; or when taken together,R_(A1) and R_(B1) form a fused aryl ring or heteroaryl ring containingone heteroatom selected from the group consisting of N and S, whereinthe aryl or heteroaryl ring is unsubstituted or substituted by one ormore R groups, or substituted by one R₃ group, or substituted by one R₃group and one R group; or when taken together, R_(A1) and R_(B1) form afused 5 to 7 membered saturated ring, optionally containing oneheteroatom selected from the group consisting of N and S, andunsubstituted or substituted by one or more R groups; R is selected fromthe group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl,alkoxy, alkylthio, and N(R₉)₂; R₂ is selected from the group consistingof: —X′—Y′—R₄′, and —X′—R₅ ¹; R₃ is selected from the group consistingof: -Z-R₄′, -Z-X′—R₄′, -Z-X′—Y′—R₄′, -Z-X′—Y′—X′—Y′—R₄′, and -Z-X′—R₅′;R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstitutedor substituted by one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,dialkylamino, and in the case of alkyl, alkenyl, alkynyl, andheterocyclyl, oxo, with the proviso that when R₁ is R₄, R₄ is asubstituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁ is bonded; R₄′ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A′ is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A″ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; X′ is selected from the groupconsisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkenylenegroups can be optionally interrupted or terminated by arylene,heteroarylene or heterocyclylene and optionally interrupted by one ormore —O— groups; Y′ is selected from the group consisting of:

Z is a bond or —O—; and c and d are independently integers from 1 to 6with the proviso that c+d is ≦7; or a pharmaceutically acceptable saltthereof.
 8. A compound of the Formula XVI:

wherein: G is selected from the group consisting of: —C(O)—R′″,α-aminoacyl, α-aminoacyl-α-aminoacyl, —C(O)—O—R′″, —C(O)—N(R″″)R′″,—C(═NY₂)—R′″, —CH(OH)—C(O)—OY₂, —CH(OC₁₋₄ alkyl)Y₀, —CH₂Y₁, and—CH(CH₃)Y₁; R′″ and R″″ are independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, phenyl, benzyl, and2-phenylethyl, each of which may be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofhalogen, hydroxy, nitro, cyano, carboxy, C₁₋₆ alkyl, C₁₋₄ alkoxy, aryl,heteroaryl, aryl-C₁₋₄ alkylenyl, heteroaryl-C₁₋₄ alkylenyl, halo-C₁₋₄alkylenyl, halo-C₁₋₄ alkoxy, —O—C(O)—CH₃, —C(O)—O—CH₃, —C(O)—NH₂,—O—CH₂—C(O)—NH₂, —NH₂, and —S(O)₂—NH₂, with the proviso that R″″ canalso be hydrogen; α-aminoacyl is an α-aminoacyl group derived from anα-amino acid selected from the group consisting of racemic, D-, andL-amino acids; Y₂ is selected from the group consisting of hydrogen,C₁₋₆ alkyl, and benzyl; Y₀ is selected from the group consisting of C₁₋₆alkyl, carboxy-C₁₋₆ alkylenyl, amino-C₁₋₄ alkylenyl, mono-N—C₁₋₆alkylamino-C₁₋₄ alkylenyl, and di-N,N—C₁₋₆ alkylamino-C₁₋₄ alkylenyl; Y₁is selected from the group consisting of mono-N—C₁₋₆ alkylamino,di-N,N—C₁₋₆ alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl,and 4-C₁₋₄ alkylpiperazin-1-yl; X₁ is a bond or C₁₋₄ alkylene; A₁ isselected from the group consisting of —N(R₈)— and —N(—Y—R₄)—; Y isselected from the group consisting of —C(R₆)—, —C(R₆)—O—, —S(O)₂—,—S(O)₂—N(R₈)—, and —C(R₆)—N(R₁₁)—; wherein R₁₁ is selected from thegroup consisting of hydrogen, alkyl, and arylalkylenyl; or R₁₁ and R₄together with the nitrogen atom to which R₁₁ is bonded can join to formthe group

A is selected from the group consisting of —CH(R₈)—, —O—, —N(R₈)—,N(Y—R₄)—, and —N(X—N(R₈)—Y—R₄)—; a and b are independently integers from1 to 4 with the proviso that when A is —O—, —N(R₈)—, —N(Y—R₄)—, or—N(X—N(R₈)—Y—R₄)— then a and b are independently integers from 2 to 4; Xis C₂₋₂₀ alkylene; R₁′ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl wherein thealkylenyl group contains at least two carbon atoms between the hydroxyor alkoxy substituent and the nitrogen atom to which R₁′ is bonded;R_(A1) and R_(B1) are each independently selected from the groupconsisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and—N(R₉)₂; or when taken together, R_(A1) and R_(B1) form a fused arylring or heteroaryl ring containing one heteroatom selected from thegroup consisting of N and S, wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R groups, or substituted byone R₃ group, or substituted by one R₃ group and one R group; or whentaken together, R_(A1) and R_(B1) form a fused 5 to 7 membered saturatedring, optionally containing one heteroatom selected from the groupconsisting of N and S, and unsubstituted or substituted by one or more Rgroups; R is selected from the group consisting of; halogen, hydroxy,alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and —N(R₉)₂; R₂ isselected from the group consisting of: —R₄′, —X′—R₄′ —X′—Y′—R₄′, and—X′—R₅′; R₃ is selected from the group consisting of: -Z-R₄′, -Z-X′—R₄′,-Z-X′-—Y′—R₄′, -Z-X′—Y′—X′—Y′—R₄′, and -Z-X′—R₅′; R₄ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl groups can be unsubstituted or substitutedby one or more substituents independently selected from the groupconsisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro,hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy,heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,dialkylamino, and in the case of alkyl, alkenyl, alkynyl, andheterocyclyl, oxo, with the proviso that when R₁ is R₄, R₄ is asubstituted alkyl group, and the substituent contains a hetero atomwhich bonds directly to the alkyl group, then the alkyl group containsat least two carbons between the substituent and the nitrogen atom towhich R₁, is bonded; R₄′ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A′ is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A″ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; X′ is selected from the groupconsisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated by arylene,heteroarylene or heterocyclylene and optionally interrupted by one ormore —O— groups; Y′ is selected from the group consisting of:

Z is a bond or —O—; and c and d are independently integers from 1 to 6with the proviso that c+d is ≦7; or a pharmaceutically acceptable saltthereof. 9-13. (canceled)
 14. The compound or salt of claim 1 wherein nis
 0. 15-17. (canceled)
 18. The compound or salt of claim 1 wherein R₁is R₄.
 19. The compound or salt of claim 18 wherein R₄ is alkyl orarylalkylenyl.
 20. The compound or salt of claim 19 wherein R₄ ismethyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-ethylpropyl,2-methylpropyl, 3-methylbutyl, benzyl, 2-phenylethyl, or 3-phenylpropyl.21. The compound or salt of claim 1 wherein R₁ is —X—N(R₈)—Y—R₄.
 22. Thecompound or salt of claim 21 wherein X is C₂₋₄ alkylene, R₈ is hydrogen,R₄ is C₁₋₆ alkyl, Y is —C(O)—, —S(O)₂—, or —C(O)—N(R₁₁)— wherein R₁₁ ishydrogen or R₁₁ and R₄ join to form a morpholine ring. 23-27. (canceled)28. The compound or salt of claim 1 wherein R₁′ is hydrogen.
 29. Thecompound or salt of claim 2 wherein R₂ is hydrogen, alkyl,alkoxyalkylenyl, or hydroxyalkylenyl. 30-31. (canceled)
 32. Apharmaceutical composition comprising a therapeutically effective amountof a compound or salt of claim 1 combination with a pharmaceuticallyacceptable carrier.
 33. A method of inducing cytokine biosynthesis in ananimal comprising administering an effective amount of a compound orsalt of claim 1 to the animal.
 34. A method of treating a viral diseasein an animal in need thereof comprising administering a therapeuticallyeffective amount of a compound or salt of claim 1 to the animal.
 35. Amethod of treating a neoplastic disease in an animal in need thereofcomprising administering a therapeutically effective amount of acompound or salt claim 1 to the animal.